Pharmaceutical compositions for preventions and managements of dementia, infectious diseases, cancers, periodontitis, dental caries, diabetes, obesity, osteoporosis and chronic pain and methods thereof

ABSTRACT

The present invention relates to the area of pharmaceutical compositions. More particularly, the present invention relates to a series of pharmaceutical compositions (PTM) containing phyto-polyphenols (P), clinical drugs with selective targets (T) and a metal ions (M) and the methods thereof for use in prevention and therapy of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndromes, osteoporosis, cancers and/or chronic pain.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication No. 62/621,028 filed on Jan. 23, 2018, the entire content ofwhich is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the area of pharmaceuticalcompositions. More particularly, the present invention relates to seriesof pharmaceutical compositions (PTM) having a polyphenols (P), aclinical drug with selective targets (T) and a metal ions (M). Thepresent invention also relates to a method for use in antimicrobialeffects against pathogens and/or for use in prevention and therapy ofinfectious diseases, neurodegenerative diseases, dementia, diabetes,obesity, metabolic syndromes, periodontitis, dental caries,osteoporosis, cancers and/or chronic pain.

BACKGROUND OF THE INVENTION

There are increasing rates in prevalence of many chronic diseases suchas infectious diseases, neurodegenerative diseases (dementia,Parkinson's disease), obesity, diabetes, osteoporosis, cancers andchronic pain in the world[1,2]. Most of these diseases still have nocurable therapeutic drugs. Recent studies suggest that the common riskfactors involved in the pathogenesis of these diseases are [2-6]: (1)proinflammation (2) oxidative stress (3) mitochondrial dysfunction (4)infection (microbiome, dysbiosis) (5) immune system dysfunction. Themost important issues are the oral- and gut-microbiome link to thesenon-curable diseases[5-12]. Because of antibiotic abuse, the drugresistant infectious diseases become an urgent issue to be overcome.

There are pleiotropic effects of phytopolyphenols, especially teapolyphenols (EGCG, theaflavins) and curcumin, which exerted antioxidant,antiinflammatory, antidiabetic, anti-obesity, anticancer,neuroprotection and antibacterial effects[13-18]. In addition, we havedemonstrated that the divalent metal ions Cu²⁺, Mn²⁺, Zn²⁺, Sr²⁺ andselenite (SeO₃ ⁻²) were active modulators on cell membrane Ca²⁺permeability, ion channels and ATPases, and thus exhibited profoundeffects on the release of neurotransmitters and influenced cellfunctions[19-22].

It has been a long time in exploration of the metal-based drugs. Forinstance, cisplatin is a Pt derivative used as an important anticancerdrug. In addition, we have reported and got an American patent (Pub.No.: US 2014/0094513) about the synergistic effects of combined EGCG andmemantine as a neuroprotectant against brain excitotoxicities (dementia)in mice[23-25].

Our strategy to combat the increasing prevalence and still no curablechronic diseases (dementia, diabetes, obesity, osteoporosis and cancer)especially the multidrug resistant infectious diseases is to develop thenovel regimens with the pleiotropic pharmacological effects.

SUMMARY OF THE INVENTION

The present invention provides a series of pharmaceutical compositionsfor use in antimicrobial effects against pathogens and/or for use inprevention and therapy of infectious diseases, neurodegenerativediseases, dementia, diabetes, obesity, metabolic syndromes,periodontitis, dental caries, osteoporosis, cancers and/or chronic pain.These pharmaceutical compositions (PTM) comprise polyphenols (P), aclinical drug with selective targets (T) and a metal ions (M).

Based on the above findings, the polyphenols and the natural productsare at least one selected from the group comprising tea polyphenols,curcumin, EGCG, theaflavin, berberine, apigenin, quercetin, tannin,catechin, chlorogenic acid, isoflavone, anthocyanidin, cocoapolyphenols, citrin, flavonoids tetramethylpyrazine,nordihydroguaiaretic acid and resveratrol etc.

According to the above, the clinical drug with selective target is atleast one selected from the group comprising antibiotics, receptoragonists or antagonists, ion channel modulators, membrane iontransporters and mitochondrial functional modulators.

According to the above, the clinical drug with selective target is atleast one selected from the group comprising NaF, memantine, metformin,thioridazine, chlorpromazine, tobramycin, rifampin, strepotomycin,isoniazide, verapamil, diltiazem, dithiothretol, dibucaine, digitonin,polymycin B, cisplatin, dequalinium, 4-hexylresorcinol, ursodeoxycholicacid, etidronate, glibenclamide and 3,4-diaminopyridine.

According to the above, the metal ions is at least one selected from thegroup comprising Cu²⁺, Mn²⁺, VO₄ ²⁺, Zn²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, Ge132 andRuR(Ruthenium red).

According to the above, the infectious pathogen is at least one selectedfrom the group comprising Porphyromonas gingivalis, Streptococcusmutans, E. coli, Pseudomonas aeruginosa, Bacillus subtilis,Staphytococcus aureus, Mycobacterium tuberculosis, etc.

According to the above, the proportion between the concentration of thepolyphenols and the clinical drug with selective target is 1:0.1-3, etc.

According to the above, an interaction between the polyphenols, theclinical drug with selective target and the metal ions leading tosynergistic effects.

In one aspect, the invention provides a method for use in antimicrobialeffects against pathogens and/or for use in prevention and therapy ofinfectious diseases, neurodegenerative diseases, dementia, diabetes,obesity, metabolic syndromes, osteoporosis, periodontitis, dentalcaries, cancers and/or chronic pain, comprising a polyphenols, aclinical drug with selective targets and a metal ion, wherein aninteraction between the polyphenols, the clinical drug with selectivetargets and the metal ions leading to synergistic effects.

According to the above, the polyphenols are at least one selected fromthe group comprising tea polyphenols, curcumin, EGCG, theaflavin,apigenin, berberine, quercetin, tannin, catechin, chlorogenic acid,isoflavone, anthocyanidin, cocoa polyphenols, citrin, flavonoid andresveratrol etc.

According to the above, the clinical drug with selective target is atleast one selected from the group comprising receptor agonists orantagonists, ion channel modulators, membrane ion transporters,mitochondrial functional modulators, immune modulators and antibiotics.

According to the above, the clinical drug with selective target is atleast one selected from the group comprising NaF, memantine, metformin,thioridazine, chlorpromazine, etidronate, clodronate, glibenclamide,3,4-diaminopyrine, verapamil, diltiazem, dithiothreitol, dibucaine,digitonin, polymycin B, tobramycin, rifampin, streptomycin, cisplatin,dequalinium, 4-hexylresorcinol, ursodeoxycholic acid, etidronate,glibenclamide and 3,4-diaminopyridine etc.

According to the above, the metal ions is at least one selected from thegroup comprising Cu²⁺, Mn²⁺, VO₄ ²⁺, Zn²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, Ge132 andRuR.

According to the above, the infectious pathogen is at least one selectedfrom the group comprising Porphyromonas gingivalis, Streptococcusmutans, E. coli, Pseudomonas aeruginosa, Bacillus subtilis andStaphytococcus aureus, MRSA and Mycobacterium tuberculosis.

According to the above, the proportion between the concentration of thepolyphenols and the clinical drug with selective target is 1:0.1-3.

The foregoing and other features or advantages of the present inventiondisclosure will be more readily appreciated by one of ordinary skilledin the art from the following figures, embodiments and descriptions.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described with reference tothe accompanying drawings. With specific reference to the drawings indetail, it is emphasized that the particulars shown are by way ofexample and for purposes of illustrative discussion of embodiments ofthe invention.

FIG. 1 shows that novel regimens enhancing the growth of Lactobacillusreuteri.

FIG. 2A shows that novel regimens increased alkaline phosphatase(ALP)and the ARS mineral contents of the cultured preosteoblast MC3T3-E1cells.

FIG. 2B shows that novel regimens increased alkaline phosphatase(ALP)and the ARS mineral contents of the cultured preosteoblast MC3T3-E1cells.

FIG. 2C shows that novel regimens increased alkaline phosphatase(ALP)and the ARS mineral contents of the cultured preosteoblast MC3T3-E1cells.

FIG. 2D shows that novel regimens increased alkaline phosphatase(ALP)and the ARS mineral contents of the cultured preosteoblast MC3T3-E1cells.

FIG. 2E shows that novel regimens increased alkaline phosphatase(ALP)and the ARS mineral contents of the cultured preosteoblast MC3T3-E1cells.

FIG. 3A shows the decreased tartrate-resistant acid phosphatase, (TRAP)activities of the novel regimens on the cultured preosteoclast RAWcells.

FIG. 3B shows the decreased tartrate-resistant acid phosphatase, (TRAP)activities of the novel regimens on the cultured preosteoclast RAWcells.

FIG. 3C shows the decreased tartrate-resistant acid phosphatase, (TRAP)activities of the novel regimens on the cultured preosteoclast RAWcells.

FIG. 3D shows the decreased tartrate-resistant acid phosphatase, (TRAP)activities of the novel regimens on the cultured preosteoclast RAWcells.

FIG. 4A shows the neuroprotective effects of novel regimens againstH₂O₂-cytotoxicity in culture neuroblastoma cell.

FIG. 4B shows the neuroprotective effects of novel regimens againstH₂O₂-cytotoxicity in culture neuroblastoma cell.

FIG. 5A shows the effects of the novel regimens on the locomotoractivities of the mice after oral administrations of the drugs.

FIG. 5B shows the effects of the novel regimens on the locomotoractivities of the mice after oral administrations of the drugs

DETAIL DESCRIPTION OF THE INVENTION

Disclosed are methods and compositions for providing a series ofpharmaceutical compositions and use thereof. The invention will be ableto be practiced by one skilled in the art that references to thefollowing embodiments and descriptions.

Based on the major common risk factors (inflammation, oxidative stress,mitochondrial metabotic dysfunction, immune dysfunction and infection)involved in the pathogenesis of the above mentioned diseases[1-6], wehave developed the novel regimens, PTM, with the advantage of theirchemical complex formations of polyphenols and metals andpharmacological interactions, leading to the synergistic effects amongthem (anti-oxidant, anti-inflammatory, anti-microbial andneuroprotection)[23-25]; P, phytopolyphenols; T, clinical drugs withselective targeting such as receptor agonists or antagonists, ionchannel modulators, membrane ion transporters, mitochondrial functionalmodulators, antibiotics etc.; M, metals such as Cu²⁺, Mn²⁺, Zn²⁺, VO₄²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, Ge132, ruthenium red etc.

Culture of Pathogens

The anaerobic pathogens, Streptococcus mutans (S.m., UA159) andPorphyromonas gingivalis (P.g.) were cultured in Brain heart infusionbroth (BHI, Becton Dickinson, Sparks, Md.) and Wilkins-Chalgren AnaerobeBroth respectively at 37±0.5° C. in the anaerobic chamber containing 10%H₂, 5% CO₂ and 85% N₂, (Forma Scientific Inc., Marietta, Ohio, USA)[26].

The other four kinds of pathogens including E. coli, Pseudomonasaeruginosa (P.a.), Bacillus subtilis (B.s.) and Staphylococcus aureus(S.a) and the probiotic Lactobacillus reuteri (L.r.) were culturedaerobically at 37±0.5° C.

Anti-Microbial Effects of Drugs on the Proliferation of Pathogens

The proliferation rate of the cultured pathogens was measured by Elisareader at optical density 600 nm (OD600). After 16 hour culture, theOD600 value of cultured pathogen was adjusted to about 0.55, whichaccounted the bacterial concentration about 1.7×10⁹ CFU/ml. The effectsof the drugs on the proliferation of the bacteria were evaluated by thechanges of OD600 after addition various concentrations of drugs (10μl/well) to 90 μl/well of the cultured bateria diluted with culturedbroth by 10⁶ fold at 1.7×10³ CFU/ml in 96 well microplates. The drugeffects were evaluated after 24 h incubation with the bacteria by thechanges of OD600 and then calculated as percentage of the controltreated with vehicle saline. The experiments were carried out intriplicate. The antibacterial effects of the drugs were quantitativelyby the concentration inhibition curves and calculated the concentrationof each drug for 50% of inhibition (IC₅₀).

Cell Culture

Cell culture medium (RPMI) and supplements were purchased from Sigma(St. Louise, USA). All culture media were supplemented with heatinactivated FBS (JRH Biosciences or Hyclone, Thermo Scientific).

OECM-1 (oral squamous cell carcinoma cell), SG(gingival epithelialcells), RAW(preosteocast) and SHSYSY(neuroblastoma) were cultured inCO₂(5%) incubate 37° C. MC3T3-E1(preosteoblast) cells were cultured ingrowth media (α-MEM with 10% FBS, 2 mM L-glutamine and 20 mM HEPES)supplemented with 10 mM β-glycerophosphate and 50 mg/L ascorbic acid.All cells were cultured at 37° C. and 5% CO₂.

Alkaline Phosphatase Assay and Alizarin Red Mineral Contents Detection

Akaline phosphatase (ALP) activity of MC3T3-E1 cell were measured by thereaction product nitrophenol of the substrate 8 mM PNPP(P-nitro-phenylphosphate) with ALP in the Na₂CO₃ buffer (pH10) at 37° C. for 30 min andquantified by OD405 nm[27].

Mineral contents of MC3T3-E1 cells was measured by the reaction withAlizarin Red (ARS) and measured OD562 nm.

Tartrate-Resistant Acid Phosphatase (TRAP) Assay

TRAP activity of RAW cells was measured by the production ofp-nitrophenol after the substrate 8 mM PNPP (P-nitrophenyl-phosphate)hydrolyzed by TRAP in 0.1 M Na acetate (pH5.7) with 40 mM Na tartrate.The absorbance at 405 nm was determined after incubation at 37° C. for30 min[28].

Neuroprotection of Drugs Against H₂O₂ Oxidative Cytotoxicity on CulturedNeuroblastoma Cells (SHSY5Y)

The cytotoxic effects of the control H₂O₂ at 0.5, 1 and 3 mM on SHSY5Ycells at 37° C. for 24 hs, were assayed by MTT test and estimated as %control cells treated with vehicles [29,30].

Neuroprotection of drugs was detected by the addition of the drugs 10min or 30 min after 1 mM H₂O₂ application, and cell survivals measuredby MTT test were compared with that treated with 1 mM H₂O₂ alone.

TruScan Photobeam Tracking

TruScan photobeam tracking are used to record behavior (walking distancein margin and center area, number of times for jumping, rest time andtotal time of walking) of mice to compute emotional alteration as wepreviously reported[31,32]. The tracking activity of depressed miceexhibits limited center area walking distance; while normal micedistributes equally in margin and center area walking distance.Additionally, the tally of jumping and standing show the exploration andcurious behavior of normal mice.

Preparation of the Drugs

(1) Preparation of Tea Polyphenols (TP):

TP were isolated by the methods described in our previousreports[13,15]. One hundred grams of green tea or black tea (produced byWangs' Tea Enterprise Co., Ltd., Taipei, Taiwan), was suspended in 1 Lof distilled water at 75° C. for 30 min; then the supernatant wascollected. This step was repeated three times. The supernatant werefiltered to eliminate chlorophylls and undissolved particle. The totalaqueous layers were concentrated to 0.5 L under reduced pressure using arotatory vacuum evaporator. The concentrated solution was extracted withan equal volume of chloroform three times to eliminate caffeine andpigments. The remaining aqueous phase was then extracted with an equalvolume of ethyl acetate three times to extract tea polyphenols. The TPin ethyl acetate was combined and evaporated in vacuum. The residue wasdissolved in a small volume of distilled water and freeze-dried. Thisgoldbrown solid matter was called tea polyphenols.

(2) Purified curcumin was purchased from Merck Co. (German),memantine(Mem), metformin(MF), etidronate(Eti), thioridazine(TRZ),chlorpromazine(CPZ), and ruthenium red(RuR) were all from Sigma ChemicalCompany (USA).(3) Assessments of the interactions in antimicrobial potencies of drugcombinations:

The potencies of antimicrobial effect of various drug combinations ascompared with that of drug alone were assessed by combination index(CI)[33].

${CI} = {\frac{\left( {IC}_{50} \right)_{1}\mspace{14mu} {in}\mspace{14mu} {combination}}{\left( {IC}_{50} \right)_{1}\mspace{14mu} {alone}} + \frac{\left( {IC}_{50} \right)_{2}\mspace{14mu} {in}\mspace{14mu} {combination}}{\left( {IC}_{50} \right)_{2}\mspace{14mu} {alone}} + \frac{\left( {IC}_{50} \right)_{3}\mspace{14mu} {in}\mspace{14mu} {combination}}{\left( {IC}_{50} \right)_{3}\mspace{14mu} {alone}}}$     CI < 1, synergism; CI = 1, addition; CI > 1, antagonism${{Potency}\mspace{14mu} {{ratio}({fold})}} = {\left( {\frac{\left( {IC}_{50} \right)_{1}\mspace{14mu} {alone}}{\left( {IC}_{50} \right)_{1}\mspace{14mu} {in}\mspace{14mu} {combination}} + \frac{\left( {IC}_{50} \right)_{2}\mspace{14mu} {alone}}{\left( {IC}_{50} \right)_{2}\mspace{14mu} {in}\mspace{14mu} {combination}} + \frac{\left( {IC}_{50} \right)_{3}\mspace{14mu} {alone}}{\left( {IC}_{50} \right)_{3}\mspace{14mu} {in}\mspace{14mu} {combination}}} \right) \times \frac{1}{3}}$

Statistics

Results for each experiment were represented as mean±SEM. One way ANOVAfollowed by a post-hoc t test was used to evaluate differences betweenthe groups. The level of significance was defined as p<0.05.

EXAMPLES 1. Antibacterial Effects of Polyphenols and Metals Either Aloneor in Combination

As shown on Tables 1A and 1B, phyto-polyphenols (EGCG, green teapolyphenols, curcumin) exhibited pleiotropic inhibitory effects on theproliferation of various cultured pathogens (P.g., UA159, P.a., S.a.)but not cinnamon. The combination of polyphenol and metalssynergistically inhibited bacterial growth more than 10 fold as revealedby IC₅₀ of metals (mM) (Table 1C). Cinnamon-metal compounds still had noeffects on bacteria growth except that cinnamon-RuR compoundssynergistically inhibited P.g. and P.a. by 2.6 and 1.3 fold respectivelyas estimated by their decreased IC₅₀.

2. Antibacterial Effects of Various Drugs and Natural Compounds Studiedin this Report:

As shown on Table.2A, among the repurposing drugs studied, dequalinium,thioridazine and chlorpromazine possessed antibacterial effects muchmore than the others (NaF, 4-hexyl-resorcinol, memantine, metformin,etidronate and quinine). The natural products (berberine, lysozyme,quercetin, tetramethylpyrazine and nordihydroguaiaretic acid) were alsoweak by themselves in anti-bacterial effects (Table 2B). However, theantibiotics (tobramycin, rifampin and streptomycin) were very potentanti-bacterial effects (Table3A), but neither nystatin nor isoniazid hadthese effects alone (Table3A). The polypeptides (polyarginine,protamine, polylysine, Arg-Phe) and toxin peptides (notexin, cobracardiotoxin, cobra phospholipase A₂ and α-bungarotoxin) were also weakin antibacterial effects except some of these peptides inhibited P.g.growth (Table 3B).

3. Potent Antibacterial Effects of Novel Regimens Containing RepurposingDrugs.

As shown on Table2A, antibacterial effects of thioridazine andchlorpromazine alone were potent in decreasing order on P.g., UA159,S.a. and P.a. Metformin alone was almost without this effect, butmarkedly increased by 20 to 80 fold in the novel regimens (Table4). EGCG(E) appeared to be better than curcumin(C) and black tea polyphenols (T)in enhancing the antibacterial potencies on the 4 pathogens studied.Among them, E-MF-Zn was the best, E-TRZ-Zn and E-CPZ-Zn the next. Theruthenium red (RuR) containing regimens were also potent especiallythose on S.a. (Table4). Further studies on the TRZ and CPZ regimenscontaining six metals (Cu²⁺, Ag⁺, Mn^(2±), VO4²⁺, Zn²⁺ and Sr²⁺), showedtheir antibacterial effects were also potent but some of them markedwith (X) were not as potent as they used alone (Table5).

4. Antibacterial Effects of Novel Regimens Containing MembraneTransporter Blockers.

As shown on Table2A, the membrane transporter blockers (verapamil,diltiazem, dithiothreitol, dibucaine and digitonin) alone were inactive,but their combinations exhibited potent antibacterial effects on P.g.and P.a. but not on UA159 and S.a. (Table 6).

5. Antibacterial Effects of Novel Regimens Containing Antibiotics andPolypeptides.

As shown on Table 3, antibiotics (tobramycin, rifampin and streptomycin)alone possessed very potent antibacterial effects but still exhibitedmore potent in some of the novel regimens (Table land 8). The regimenscontaining polymycin B (PM) also appeared promising potent (Table7).Although nystatin and isoniazid alone were almost inactive but becamepotent antibacterial in the novel regimens (Table 7). The polypeptidesor toxin polypeptides combined with E-Q, E-F or E-R shown on Table 9were extraordinarily potent in inhibiting the proliferation of P.g.,UA159 and P.a. but not S.a. excepting that E-Q(F,R) RF were very potentin inhibiting S.a. On the other hand, the combinations of polypeptideswith E-metals were less potent about 1/10 of the potency of the regimenas mentioned above containing E-Q, E-F or E-R(Tables 9 and 10).

6. Antibacterial Effects of Novel Regimens Containing Memantine,Metformin and Natural Products.

Although both memantine and metformin were almost inactive inantibacterial effects (Table 2A), they markedly synergistically exertedthese effects in combination with various polyphenols-metallic compounds(Table 11). Similarly, the natural compounds (berberine, quercetin,tetramethylpyrazine and nordihydroguaiaretic acid) were by themselvesvery weak in antibacterial efficacy (Table 2B), but they markedly,synergistically exerted antibacterial effects in combination withpolyphenolic-metallic compounds (Table 12).

7. Antibacterial Effects of Novel Regimens Containing Etidronate,Glibenclamide (Gbc) and 3,4-Diaminopyridine (3,4-DAP).

As shown on Table 13, the combinations of etidronate (Eti),glibenclamide (Gbc) and 3,4-diaminopyridine (3,4-DAP) withpolyphenolic-metallic compounds also revealed promising antibacterialeffects especially the regimen of C⋅Eti⋅metals were very potent ininhibiting proliferation of S.a. (Table 13A). Addition of memantineenhanced the antibacterial efficacy on P.g. of regimens containing Gbcor 3,4-DAP by about 2 fold (Table 13C).

8. Antibacterial Effects of Novel Regimens Containing Ag, Ge132 andCisplatin (Pt).

As shown on Table 14, novel regimens containing Ag, Ge132 and cisplatin(Pt) exerted better antibacterial efficacy especially on P.a. and S.a.

9. Antibacterial Effects of the Mixtures of Herb Extracts

The mixtures of herb extracts (either GIM: the extract mixtures of Amlagooseberry, Rosehip fruit and yeast GSH; or OP, extract mixtures ofbilberry, cassia seed, xangold and boxthorn combined with EGCG, licoriceand peppermint oil, were found to be as potent as berberine andquercetin in their antibacterial effects (Table 15).

10. Selectivity of the Antibacterial Effects of the Novel RegimensStudied.

We have demonstrated that among the 282 effective antibacterial regimenstested, 83% of these effective regimens on the cultured pathogens werenot inhibited on the proliferation of probiotic Lactobacillus reuteri(L.r.) even at the concentrations 3-10 times higher than IC₅₀ of eachregimen respectively. Actually, some of these regimens especially thosecontaining MnCl₂ markedly increased the L.r. growth (FIG. 1). In FIG. 1,final concentrations (1×: mg/ml·mg/ml·mM) of drug combinations are asfollowing:

-   -   NaF: 1 mg/ml    -   EQCu:0.1·0.0003·0.03    -   EQMn:0.1·0.0003·0.03    -   EFCu:0.1·0.03·0.03    -   EFMn:0.1·0.03·0.03    -   EFSr:0.1·0.03·0.1

11. Selective Anticancer Effects of the Novel Regimens.

As shown on Table 16, the novel regimens containing VO₄ ²⁻ and RuRexerted more potent inhibitory effects on the cultured oral squamouscarcinoma cells (OECM-1) as compared with those on the gingivalkeratinocytes SG cell line.

12. Increased Osteogenic Activities of the Novel Regimens:

As shown on FIG. 2A-2E, the novel regimens containing EGCG with thetargeting drugs either dequalinium(Q), NaF(F), 4-hexyl-resorcinal(R),Memantine(mem), glibenclamide(Gbc) or 3,4-diaminopyridine(3,4-DAP) andthe metal ions(ZnCl₂, SrCl₂ or Ge132) could alter cell proliferation,alkaline phosphatase (ALP) activities and ARS mineral contents ofcultured MC3T3-E1 cells.

It appeared that E-Mem-Sr, E-Q-Sr, E-R-Zn, E-Gbc-Zn(or Ge) andE-3,4-DAP-Sr were potent in increasing alkaline phosphatase activitiesof the cultured MC3T3-E1 cells. On the other hand, E-Q-Mem, E-F-Sr,E-Eti-Zn, E-Gbc-Mem.Sr and E-3,4-DAP-Sr±Mem increased the ARS mineralcontents of the cultured MC3T3-E1 cells.

FIG. 2A-2E. Novel regimens increased alkaline phosphatase(ALP) and theARS mineral contents of the cultured preosteoblast MC3T3-E1 cells.

Final concentrations of each drug combinations at one fold (1×,mg/ml·mg/ml·mM) are as following:

EMemZn, EEtiZn:0.1·0.1·0.1; EMemSr, EEtiSr:0.1·0.1·0.3; EQ:0.15·0.0005;

ER:0.15·0.0075 mg/nal; EQMem:0.1·0.0003·0.1 mg/ml; ERMem:0.1·0.005·0.1mg/ml; EQZn:0.03·0.0001·0.01; EQSr:0.03·0.0001·0.03;EFZn:0.03·0.01·0.01;

EFSr:0.03·0.01·0.03; ERZn:0.1·0.005·0.03; EGbcZn:0.1·0.00066·0.1;EGbcSr:0.1·0.00066·0.3; EGbcGe:0.1·0.00066·0.033;

EGbcZnMem:0.075·0.0005·0.075·0.075 mg/ml;EGbcGeMem:0.075·0.0005·0.025·0.075 mg/nal;EGbcSrMem:0.075·0.0005·0.225·0.075 mg/ml; E34DAPZn:0.1·0.03·0.1;

E34DAPSr:0.1·0.03·0.3; E34DAPGe:0.1·0.03·0.03;

E34DAPZnMem:0.075·0.025·0.075·0.075 mg/ml;E34DAPSrMem:0.075·0.025·0.225·0.075 mg/ml;E34DAPGeMem:0.075·0.025·0.025·0.075 mg/ml.

13. Decreased Osteoclastogenic Effects of the Novel Regimens:

As shown on FIG. 3A-3D, E-Eti-SeO₃(VO₄) and E-Clo-VO₄(Zn,Sr) decreasedtartrate-resistant acid phosphatase activities of the culturedpreosteoblast RAW cells. Final concentrations (1×: mg/ml·mg/ml·mM) ofeach drug combinations are as following:

EEtiCu:0.1·0.1·0.1 EEtiSe(Mn,VO4,Zn): 0.1·0.1·0.1 EEtiSr: 0.1·0.1·0.3ECloCu: 0.1·0.3·0.1 ECloSe(Mn,VO4,Zn): 0.1·0.3·0.1 ECloSr: 0.1·0.3·0.314. Neuroprotective Effects of the Novel Regimens:

As shown on FIGS. 4A and 4B, the cytotoxic effects of H₂O₂ on culturedneuroblastoma SHSYSY cells could be reduced by the regimens ofE-TRZ(CPZ,MF)-RuR; T-MF(Eti)-RuR; E-C(Mem)-Zn and G-Mem-Zn respectively.The neuroprotective effects of the drugs are studied after 10 min(A) and30 min(B) of H2O2 added to the cultured cell.

The concentration of H2O2 are 0.5, 1 and 3 mM respectively for thecytotoxicity test. Final concentrations of each drug combinations at onefold (1×, mg/ml·mg/ml·mM) are as following:

ETRZRuR, ECPZRuR:0.3·0.03·0.035; EEtiRuR:0.3·0.3·0.035;TMFRuR:0.1·0.1·0.035; TEtiRuR:0.1·0.3·0.035; ECZn, EMemZn,GMemZn:0.1·0.03·0.03; EMFRuR:0.3·0.1·0.035. 15. Safety of Novel Regimensin Mice and Zebrafish:

The drug combinations (C-TRZ(CPZ,MF)-Zn(RuR) were orally administratedto mice for 3 weeks showed safe and both C-TRZ(MF)-RuR slightlyincreased the locomotor activities (FIGS. 5A and 5B). Toxicity tests ofregimens in zebrafish showed zero mortality after intramuscularinjections for 1-5 days. In FIGS. 5A and 5B, final concentrations ofeach drug combinations at one fold (1×, mg/ml·mg/ml·mM) are asfollowing:

CTRZZn, CCPZZn:0.1·0.01·0.03; CTRZRuR, CCPZRuR: 0.1·0.01·0.035;CMFZn:0.1·0.1·0.03; CMFRuR:0.1·0.1·0.035.

Potential Applications of these Novel Regimens

1. Gut-Brain and oral cavity microbiomes have been extensively studiedtheir relevance to human health and diseases (periodontitis, dementia,neurodegenerative diseases, diabetes, obesity, metabolic syndromes,inflammatory bowel disease, osteoporosis, cancers etc.). The novelregimens possessed not only anti-pathogenic effects but also enhancedthe growth of probiotics, suggesting that they have a potential to alterthe dysbiosis state to human homeostatic microbiome, leading toalleviate diseases and enhance healthy status.

2. Potential Applications in Management of Infections Diseases:

The various novel regimens showed pleiotropic inhibitory effects on thecultured pathogens. Recently, we cooperated with Drs. H. Y. Dou and T.L. Yang (Nat: Inst. Infectious Dis. And Vaccinology, Nat. Health Res.Institute (NHRI), Taiwan) to test the inhibitory effects of C-TRZ (CPZ,MF)-RuR on the multi-drug resistant (MDR) bacteria. A preliminary resultshowed that these novel regimens were effective in inhibiting theproliferation of MDR-Mycobacterium tuberculosis, MRSA and MDR-Efalcalis.

3. Potential Applications in Neurodegenerative Diseases:

Our previous studies have shown that EGCG was synergisticallywithmemantine for attenuating mouse CNS neuroexcitotoxicity.

The novel regimens of E(C,G)-Mem-Metals were proposed to exert bothneuroprotection and modulation on oral microbiome (decreasedperiodonitis) which may be benefial to managements of dementia,Parkinson's diseases and other neurogenerative disease. Similarly, E(T)-TRZ (CPZ,MF,Eti)-RuR exhibited neuroprotective effects against H₂O₂oxidative cytotoxicity. Thus, they may have the potential benefit forprevention of these neurodegenerative diseases.

4. Prevention and Therapy of Metabolic Syndromes, Diabetes and Obesity.

The regimens containing metformin (E(C, G)-MF-Zn (RuR)) would bepotentially more effective than metformin alone for prevention andtreatment of these metabolic diseases.

5. For Prevention and Therapy of Osteoporosis.

The novel regimens containing etidronate, Zn²⁺, Sr²⁺, memantine,glibenclamide(Gbc) and 3,4-diaminopyridine revealed to be promising inincreasing alkaline phosphatase(ALP) activities of the preosteoblast(MC3T3-E1) cells (FIG. 2A-2E), while E, Eti(Clo)VO4 and E, Clo, Zn(Sr)decreased tartrate resistant acid phosphatase(TRAP) activities ofpreosteoclast (RAW) cells (FIG. 3A-3D). These regimens may havepotential application for prevention and therapy of osteoporosis.

6. For Prevention and Therapy of Cancers:

The selective anticancer effects of the novel regimen on the culturedoral cancer cells (OECM-1) as revealed in table 17 may have potentialapplication in prevention and therapy of cancers.

7. For Prevention and Therapy of Chronic Pain:

We have previously reported that combinations of tea polyphenols andMemantine were effective not only in attenuating oralfacial pain butalso suppressed morphine analgesic tolerance. The regimens of E(C,G)-Mem(MF)-Metals especially with RuR were expected to be effective inprevention and therapy of chronic pain.

Our experimental results (Tables 1 to 17) indicate that combination oftea polyphenol EGCG and memantine synergistically protected the brainagainst excitotoxicity (a cause of dementia, an American patent, PubNo.: US 2014/0094513). A series of different trial combinations (Tables1, 2 and 3) containing EGCG (E), curcumin (C), green tea polyphenols(G), cinnamon (CC) or theaflavins (T), combined with memantine (Mem),metformin (MF), thioridazine (TRZ), chlorpromazine (CPZ),tobramycinrifampin, strepotomycin, isoniazide, verapamil, diltiazem,dithiothretol, dibucaine, cisplatin, dequalinium, 4-hexylresorcinol,ursodeoxycholic acid or etidronate (Eti) plus metal ion; either Cu²⁺,Mn²⁺, Zn²⁺, VO₄ ²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, Ge132 or ruthenium red (RuR)revealed a synergistic broad spectrum potent anti-microbial effectsagainst Porphyromonas gingivalis (P.g.), Streptococcus mutans (UA159),E. coli, Pseudomonas aeruginosa (P.a.), Bacillus subtilis (B.s.),Staphytococcus aureus (S.a.) accompanied with anticancer effect(OECM-1). We believe that these novel regimens provide the safetherapeutic armamentarium to combat these incurable diseases.

The invention includes embodiments in which exactly one member of thegroup is present in, employed in, or otherwise relevant to a givenproduct or process. The invention includes embodiments in which morethan one, or all of the group members are present in, employed in, orotherwise relevant to a given product or process.

Those skilled in the art will recognize, or be able to ascertain byusing no more than routine experimentation, many equivalents to thespecific embodiments of the invention, described herein. The scope ofthe present invention is not intended to be limited to the particularembodiments disclosed, but rather includes all embodiments fallingwithin the scope of the appended claim. In addition, many modificationswill be appreciated to adapt a particular instrument, situation ormaterial to the teachings of the invention without departing from theessential scope thereof.

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TABLE 1 Concentrations of polyphenols, metalions and polyphenol-metalcombimetal salts for 50% inhibitions on antibacterial effects (IC₅₀). A.IC₅₀ (mg/ml) Polyphenols P. g. UA159 P. a. S. a. E, EGCG 0.083 0.1370.173 0.142 G, Green tea 0.044 0.135 0.180 0.384 polyphenols T*, Blacktea 0.167 0.124 0.291 0.150 polyphenols C*, Curcumin 0.126 0.042 0.302<1 CC, cinnamon >0.3 >0.3 >0.3 >0.3 B. IC₅₀ (mM) Metals P. g. UA159 P.a. S. a. CuCl₂ 0.673 0.448 1.691 >2 AgCl* 0.014 0.035 0.044 0.028 MnCl₂*0.990 1.435 >2 2.742 Na₃VO₄ 0.217 0.866 >2 >2 ZnSO₄* 1.063 0.961 1.1590.939 SrCl₂* >3 >3 4.193 3.593 RuR*, 0.074 0.644 0.032 >0.116 Rutheniumred C. IC₅₀ (mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E · Cu* 0.113 ·0.013 0.113 · 0.013 0.092 · 0.010 0.091 · 0.010 E · Ag* 0.122 · 0.0140.134 · 0.004 0.096 · 0.003 0.122 · 0.004 E · Mn* 0.095 · 0.011 0.141 ·0.016 0.090 · 0.010 0.117 · 0.013 E · VO₄* 0.081 · 0.009 0.143 · 0.16 0.084 · 0.009 0.175 · 0.019 E · Zn* 0.066 · 0.007 0.098 · 0.011 0.085 ·0.009 0.121 · 0.013 E · Sr* 0.076 · 0.025 0.098 · 0.033 0.084 · 0.0280.127 · 0.042 E · RuR* 0.052 · 0.020 0.057 · 0.022 0.032 · 0.013 0.059 ·0.023 C · Cu 0.032 · 0.011 0.036 · 0.012 0.111 · 0.037 0.053 · 0.018 C ·Ag* 0.107 · 0.011 >0.15 · 0.015 >0.15 · 0.015 >0.15 · 0.015 C ·Mn* >0.15 · 0.05  >0.15 · 0.05  >0.15 · 0.05  >0.15 · 0.05  C · VO₄0.066 · 0.022 0.048 · 0.016 0.088 · 0.029 0.046 · 0.015 C · Zn* >0.15 ·0.05  >0.15 · 0.05  >0.15 · 0.05  >0.15 · 0.05  C · Sr* >0.15 ·0.15  >0.15 · 0.15  >0.15 · 0.15  >0.15 · 0.15  C · RuR 0.105 · 0.0410.049 · 0.019 0.043 · 0.016 0.051 · 0.020 G · Cu* 0.039 · 0.006 0.107 ·0.018 0.340 · 0.057 >0.3 · 0.05 G · Ag* 0.017 · 0.001 0.101 · 0.0050.131 · 0.007  >0.3 · 0.015 G · Mn* 0.025 · 0.004 0.112 · 0.019 0.126 ·0.021 >0.3 · 0.05 G · VO₄* 0.052 · 0.009 0.436 · 0.073 >0.3 · 0.05 >0.3· 0.05 G · Zn* 0.022 · 0.004 0.112 · 0.019 0.146 · 0.024 >0.3 · 0.05 G ·Sr* 0.027 · 0.013 0.101 · 0.051 0.139 · 0.069 >0.3 · 0.15 G · RuR* 0.021· 0.013 >0.15 · 0.058 0.039 · 0.022 >0.15 · 0.058 T · Cu* 0.111 · 0.0370.072 · 0.024 >0.15 · 0.05  >0.15 · 0.05  T · Ag* 0.048 · 0.005 0.194 ·0.019 >0.15 · 0.015 >0.15 · 0.015 T · Mn* 0.099 · 0.033 >0.15 ·0.05  >0.15 · 0.05  >0.15 · 0.05  T · VO₄* 0.032 · 0.011 >0.15 ·0.05  >0.15 · 0.05  >0.15 · 0.05  T · Zn* 0.045 · 0.015 >0.15 · 0.05 0.149 · 0.050 >0.15 · 0.05  T · Sr* 0.070 · 0.070 0.121 · 0.121 >0.15 ·0.15  >0.15 · 0.15  T · RuR* 0.124 · 0.048 0.029 · 0.012 0.053 ·0.021 >0.15 · 0.058 CC · Cu* >0.15 · 0.05  >0.15 · 0.05  >0.15 ·0.05  >0.15 · 0.05  CC · Ag* >0.15 · 0.015 >0.15 · 0.015 >0.15 ·0.015 >0.15 · 0.015 CC · Mn* >0.15 · 0.05  >0.15 · 0.05  >0.15 ·0.05  >0.15 · 0.05  CC · VO₄* >0.15 · 0.05  >0.15 · 0.05  >0.15 ·0.05  >0.15 · 0.05  CC · Zn* >0.15 · 0.05  >0.15 · 0.05  >0.15 ·0.05  >0.15 · 0.05  CC · Sr* >0.15 · 0.15  >0.15 · 0.15  >0.15 ·0.15  >0.15 · 0.15  CC · RuR* 0.049 · 0.028 >0.15 · 0.058 0.042 ·0.024 >0.15 · 0.058 P. g., Porphyromobas gingivalis; UA159,Streptococcus mutans; P. a., Pseudomonas aeruphosa; S. a.,Staphylococcus aureus. IC₅₀, concentrations of 50% inhibition onbacterial proliferation. *The drug combinations listed in this table atconcentrations of 3 to 10 times higher than the listed IC₅₀ have noinhibition on the proliferation of the cultured Lactobacillus reuteti

TABLE 2 Concentrations of repurposing drugs (A) and natural products (B)for 50% inhibitions on bacterial proliferation (IC₅₀). IC₅₀ (mg/ml)Drugs P. g. UA159 P. a. S. a. A. DQ, Dequalinium 0.003 0.001 >0.01 0.002F, NaF 0.666 0.01 R, 4-Hexyl- 0.020 0.015 >0.1 0.032 Resorcinol Mem,Memantine 0.059 0.386 0.321 0.435 MF, Metformin* 0.639 >1 >1 >1 TRZ,Thioridazine* 0.006 0.012 0.104 0.013 CPZ, Chlorpromazine* 0.005 0.0070.149 0.012 Eti, Etidronate 0.046 0.597 >1 0.350 Qn, Quinine0.043 >0.1 >0.1 >0.1 VP, Verapamil 0.137 >0.3 >0.3 >0.3 Di, Diltiagem0.104 >0.3 >0.3 >0.3 DT, Dithiothreitol >0.3 >0.3 >0.3 >0.3 DG,Digitonin 0.123 >0.3 >0.3 >0.3 B. Bb, Berberine >0.1 0.025 >0.1 >0.1 Lz,Lysozyme 0.021 >0.1 >0.1 >0.1 Qc, Quercetin >0.1 0.046 >0.1 >0.1 TMP,0.037 >0.3 >0.3 >0.3 Tetramethyl-pyrazine NDGA, <0.03 0.050 >0.3 0.066Nordihydro-guaiaretic acid P. g., Porphyromonas gingivalis; UA159,Streptococcus mutans; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus. IC₅₀, concentrations of 50% inhibition onbacterial proliferation. * The drug combinations listed in this table atconcentrations of 3 to 10 times higher IC₅₀ have no inhibition on theproliferation of the cultured Lactobacillus reuteri

TABLE 3 Concentrations of antibiotics (A) and polypeptides (B) for 50%inhibitions on bacterial proliferation (IC₅₀). IC₅₀ (mg/ml) P. g. UA159P.a. S. a. A. Antibiotics Tb, Tobramycin 0.004 <0.003 0.009 <0.003 Ny,Nystatin 0.228 >0.3 >0.3 >0.3 INH, Isoniazid >0.3 >0.3 >0.3 >0.3 Rf,Rifampin 4.5 × 10⁻⁴ 0.13 × 10⁻⁴ 0.026 0.13 × 10⁻⁴ St, Streptomycin 0.0090.021 0.005   2 × 10⁻⁴ B. Polypeptides PR, polyarginine0.025 >0.1 >0.1 >0.1 Pro, protamine 0.031 >0.1 >0.1 >0.1 PK37,polylysine37 0.086 >0.1 >0.1 >0.1 PK84, polylysine840.050 >0.1 >0.1 >0.1 RF, ArgPhe >0.1 >0.1 >0.1 >0.1 NTX,Notexin >0.01 >0.01 >0.01 >0.01 CTX14, Cardiotoxin0.011 >0.01 >0.01 >0.01 PLA2, Phospholipase >0.01 >0.01 >0.01 >0.01 A₂α-BuTx, >0.01 >0.01 >0.01 >0.01 α-Bungarotoxinβ-BuTx, >0.03 >0.03 >0.03 >0.03 β-Bungarotoxin P. g., Porphyromonasgingivalis; UA159, Streptococcus mutans; P. a., Pseudomonas aeruginosa;S. a., Staphylococcus aureus IC₅₀, concentrations of 50% inhibition onbacterial proliferation.

TABLE 4 Antibacterial effects of norvel regimens of repurposing drugs.IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E · TRZ · Zn*0.01 · 0.0003 · 0.001 0.130 · 0.004 · 0.013 0.066 · 0.002 · 0.007 0.159· 0.005 · 0.016 E · CPZ · Zn* 0.021 · 0.001 · 0.002 0.161 · 0.005 ·0.016 0.062 · 0.002 · 0.006 0.168 · 0.006 · 0.017 E · MF · Zn 0.012 ·0.004 · 0.001 0.111 · 0.037 · 0.011 0.061 · 0.020 · 0.006 0.153 · 0.051· 0.015 E · TRZ · RuR 0.024 · 0.001 · 0.002 0.114 · 0.004 · 0.013 0.047· 0.002 · 0.006 0.143 · 0.005 · 0.016 E · CPZ · RuR 0.015 · 0.001 ·0.001 0.082 · 0.003 · 0.009 0.021 · 0.002 · 0.006 0.136 · 0.005 · 0.016E · MF · RuR 0.028 · 0.009 · 0.003 0.109 · 0.036 · 0.013 0.044 · 0.015 ·0.005 0.132 · 0.044 · 0.015 C · TRZ · Zn* 0.034 · 0.003 · 0.010 0.021 ·0.002 · 0.006 >0.1 · 0.01 · 0.03 >0.1 · 0.01 · 0.03 C · CPZ · Zn* 0.026· 0.003 · 0.008 0.021 · 0.002 · 0.006 >0.1 · 0.01 · 0.03 >0.1 · 0.01 ·0.03 C · MF · Zn 0.032 · 0.032 · 0.009 0.027 · 0.027 · 0.008 >0.1 · 0.1· 0.03 >0.1 · 0.1 · 0.03 C · TRZ · RuR 0.021 · 0.002 · 0.007 0.027 ·0.003 · 0.009 0.030 · 0.003 · 0.010 0.038 · 0.004 · 0.013 C · CPZ · RuR0.019 · 0.002 · 0.007 0.023 · 0.002 · 0.008 0.031 · 0.003 · 0.010 0.041· 0.004 · 0.014 C · MF · RuR 0.023 · 0.023 · 0.008 0.022 · 0.022 · 0.0080.040 · 0.040 · 0.014 0.039 · 0.039 · 0.014 T · TRZ · RuR* 0.038 · 0.012· 0.014 0.037 · 0.011 · 0.013 0.036 · 0.011 · 0.013 >0.1 · 0.03 · 0.035T · Mem3 · RuR* 0.040 · 0.040 · 0.014 0.045 · 0.045 · 0.015 0.035 ·0.035 · 0.012 >0.1 · 0.1 · 0.035 T · MF · RuR* 0.040 · 0.040 · 0.0140.135 · 0.135 · 0.048 0.035 · 0.035 · 0.012 >0.1 · 0.1 · 0.035 T · CPZ ·RuR* 0.027 · 0.008 · 0.009 0.033 · 0.010 · 0.012 0.034 · 0.010 ·0.012 >0.1 · 0.03 · 0.035 T · Mem1 · RuR* 0.038 · 0.012 · 0.014 0.049 ·0.015 · 0.017 0.039 · 0.012 · 0.014 >0.1 · 0.03 · 0.035 T · Eti · RuR*0.029 · 0.088 · 0.010 0.270 · 0.881 · 0.094 0.026 · 0.077 · 0.009 >0.1 ·0.3 · 0.035 P. g., Porphyromonas gingivalis; UA159, Streptococcusmutans; P. a., Pseudomonas aeruginosa; S. a., Staphylococcus aureusIC50, concentrations of 50% inhibition on bacterial proliferation. *Thedrug combinations listed in this table at concentrations of 3 to 10times higher than the listed IC₅₀ have no inhibition on theproliferation of the cultured Lactobacillus reuteri.

TABLE 5 Antibacterial effects of thioridazine (TRZ) and chlopromazine(CPZ) regimens. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a.E · TRZ · Cu* 0.052 · 0.005 · 0.015 0.029 · 0.003 · 0.009 0.183 · 0.018· 0.055 0.048 · 0.005 · 0.014 E · TRZ · Ag* 0.056 · 0.006 · 0.006 0.024· 0.002 · 0.002 0.088 · 0.008 · 0.008 0.043 · 0.004 · 0.004 E · TRZ ·Mn* 0.084 · 0.008 · 0.025 0.069 · 0.007 · 0.021 0.132 · 0.013 · 0.0390.041 · 0.004 · 0.012 E · TRZ · VO₄* 0.018 · 0.002 · 0.005 >0.1 · 0.01 ·0.03 >0.1 · 0.01 · 0.03 0.194 · 0.019 · 0.058 E · TRZ · Zn* 0.043 ·0.004 · 0.013 0.052 · 0.005 · 0.016 0.662 · 0.066 · 0.199 0.076 · 0.008· 0.023 E · TRZ · Sr* >0.1 · 0.01 · 0.1 0.056 · 0.006 · 0.056 0.098 ·0.010 · 0.098 0.060 · 0.006 · 0.060 C · TRZ · Cu* 0.042 · 0.004 · 0.0130.130 · 0.013 · 0.039 0.151 · 0.015 · 0.045 0.028 · 0.003 · 0.008 C ·TRZ · Ag* 0.032 · 0.003 · 0.003 0.084 · 0.008 · 0.008 0.066 · 0.007 ·0.007 0.025 · 0.003 · 0.003 C · TRZ · Mn* 0.030 · 0.003 · 0.009 0.052 ·0.005 · 0.016 0.240 · 0.024 · 0.072 0.074 · 0.007 · 0.022 C · TRZ · VO₄0.018 · 0.002 · 0.005 0.147 · 0.015 · 0.044 0.226 · 0.023 · 0.068 0.031· 0.003 · 0.009 C · TRZ · Zn* 0.019 · 0.002 · 0.006 >0.1 · 0.01 · 0.030.109 · 0.011 · 0.033 0.024 · 0.002 · 0.007 C · TRZ · Sr* 0.016 · 0.002· 0.016 0.626 · 0.063 · 0.626 0.171 · 0.017 · 0.171 0.030 · 0.003 ·0.030 E · CPZ · Cu 0.023 · 0.007 · 0.023 0.024 · 0.007 · 0.024 0.080 ·0.024 · 0.080 E · CPZ · Ag 0.015 · 0.005 · 0.010 0.026 · 0.008 · 0.0170.053 · 0.016 · 0.053 E · CPZ · Mn 0.019 · 0.006 · 0.019 0.191 · 0.057 ·0.191 0.046 · 0.014 · 0.046 E · CPZ · VO₄ 0.023 · 0.007 · 0.023 0.135 ·0.040 · 0.135 >0.1 · 0.03 · 0.1 E · CPZ · Zn* 0.029 · 0.009 · 0.0290.036 · 0.011 · 0.036 0.046 · 0.014 · 0.046 E · CPZ · Sr 0.025 · 0.008 ·0.076 0.034 · 0.010 · 0.101 0.039 · 0.012 · 0.116 C · CPZ · Cu 0.089 ·0.009 · 0.027 0.009 · 0.009 · 0.030 0.126 · 0.013 · 0.038 0.078 · 0.008· 0.023 C · CPZ · Ag 0.038 · 0.004 · 0.004 0.011 · 0.011 · 0.025 0.063 ·0.006 · 0.006 0.071 · 0.007 · 0.007 C · CPZ · Mn* 0.078 · 0.008 · 0.0230.011 · 0.011 · 0.036 0.082 · 0.008 · 0.025 0.045 · 0.004 · 0.013 C ·CPZ · VO₄ 0.125 · 0.013 · 0.038 >0.03 · 0.03 · 0.1 0.086 · 0.009 · 0.0260.042 · 0.004 · 0.013 C · CPZ · Zn* 0.110 · 0.011 · 0.033 0.011 · 0.011· 0.037 0.048 · 0.005 · 0.015 0.038 · 0.004 · 0.011 C · CPZ · Sr* 0.097· 0.010 · 0.097 0.010 · 0.010 · 0.103 0.057 · 0.006 · 0.057 0.046 ·0.005 · 0.046 P. g., Porphyromonas gingivalis; UA159, Streptococcusmutans; P. a., Pseudomonas aeruginosa; S. a., Staphylococcus aureusIC₅₀, concentrations of 50% inhibition on bacterial proliferation. *Thedrug combinations listed in this table at concentrations of 3 to 10times higher than the listed IC₅₀ have no inhibition on theproliferation of the cultured Lactobacillus reuteri.

TABLE 6 Antibacterial effects of novel regimens containing membranetransporter blockers. IC₅₀ (mg/ml · mg/ml · mg/ml) Drugs P. g. UA159 P.a. S. a. E · VP · Cu** 0.021 · 0.006 · 0.006 0.094 · 0.028 · 0.028 0.062· 0.019 · 0.019 >0.1 · 0.03 · 0.03 E · VP · Mn 0.019 · 0.006 · 0.0060.050 · 0.015 · 0.015 0.054 · 0.016 · 0.016 >0.1 · 0.03 · 0.03 E · VP ·Zn 0.014 · 0.004 · 0.004 >0.1 · 0.03 · 0.03 0.054 · 0.016 · 0.016 >0.1 ·0.03 · 0.03 C · VP · Cu 0.060 · 0.018 · 0.018 >0.1 · 0.03 · 0.03 0.059 ·0.018 · 0.018 >0.1 · 0.03 · 0.03 C · VP · Mn 0.040 · 0.012 · 0.012 >0.1· 0.03 · 0.03 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 C · VP · Zn 0.040 ·0.012 · 0.012 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 E· Q · VP 0.013 · 0.00004 · 0.004 >0.1 · 0.0003 · 0.03 0.042 · 0.0001 ·0.013 >0.1 · 0.0003 · 0.03 E · F · VP 0.01 · 0.004 · 0.004 >0.1 · 0.03 ·0.03 0.04 · 0.013 · 0.013 >0.1 · 0.03 · 0.03 E · R · VP 0.013 · 0.001 ·0.004 0.075 · 0.004 · 0.022 0.041 · 0.002 · 0.012 >0.1 · 0.005 · 0.03 E· Q · Di 0.011 · 0.00003 · 0.003 >0.1 · 0.0003 · 0.03 0.047 · 0.0001 ·0.014 >0.1 · 0.0003 · 0.03 E · F · Di 0.01 · 0.003 · 0.003 >0.1 · 0.03 ·0.03 0.05 · 0.016 · 0.016 >0.1 · 0.03 · 0.03 E · R · Di 0.008 · 0.0004 ·0.002 0.089 · 0.004 · 0.027 0.047 · 0.002 · 0.014 >0.1 · 0.005 · 0.03 E· Q · DT 0.026 · 0.0001 · 0.008 >0.1 · 0.0003 · 0.03 0.087 · 0.0003 ·0.026 >0.1 · 0.0003 · 0.03 E · F · DT 0.03 · 0.009 · 0.009 >0.1 · 0.03 ·0.03 0.087 · 0.026 · 0.026 >0.1 · 0.03 · 0.03 E · R · DT 0.021 · 0.001 ·0.006 0.045 · 0.002 · 0.013 0.077 · 0.004 · 0.023 >0.1 · 0.005 · 0.03 E· Q · DB 0.025 · 0.0001 · 0.008 >0.1 · 0.0003 · 0.03 0.076 · 0.0002 ·0.023 >0.1 · 0.0003 · 0.03 E · F · DB 0.023 · 0.007 · 0.007 >0.1 · 0.03· 0.03 0.078 · 0.023 · 0.023 >0.1 · 0.03 · 0.03 E · R · DB 0.019 · 0.001· 0.006 0.041 · 0.002 · 0.012 0.085 · 0.004 · 0.025 >0.1 · 0.005 · 0.03E · Q · DG 0.016 · 0.00005 · 0.005 >0.1 · 0.0003 · 0.03 0.041 · 0.0001 ·0.012 >0.1 · 0.0003 · 0.03 E · F · DG 0.02 · 0.005 · 0.005 0.14 · 0.041· 0.041 0.04 · 0.013 · 0.013 >0.1 · 0.03 · 0.03 E · R · DG 0.013 · 0.001· 0.004 0.086 · 0.004 · 0.026 0.043 · 0.002 · 0.013 >0.1 · 0.005 · 0.03E · Q · DF 0.018 · 0.0001 · 0.005 >0.1 · 0.0003 · 0.03 >0.1 · 0.0003 ·0.03 >0.1 · 0.0003 · 0.03 E · F · DF 0.029 · 0.009 · 0.009 >0.1 · 0.03 ·0.03 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 E · R · DF 0.016 · 0.001 ·0.005 0.084 · 0.004 · 0.025 >0.1 · 0.005 · 0.03 >0.1 · 0.005 · 0.03 P.g., Porphyromonas gingivalis; UA159, Streptococcus mutans; P. a.,Pseudomonas aeruginosa; S. a., Staphylococcus aureus IC₅₀,concentrations of 50% inhibition on bacterial proliferation. **Theconcentrations of metal ions are expressed in mM

TABLE 7 Antibacterial effects of novel regimens containing antibiotics.IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E · Tb · Cu0.021 · 0.001 · 0.006 <0.01 · 0.0003 · 0.003 0.118 · 0.004 · 0.035 0.010· 0.0003 · 0.003 E · Tb · Mn 0.018 · 0.001 · 0.005 <0.01 · 0.0003 ·0.003 0.077 · 0.002 · 0.023 0.009 · 0.0003 · 0.003 E · Tb · Zn 0.017 ·0.001 · 0.005 <0.01 · 0.0003 · 0.003 0.113 · 0.003 · 0.034 0.010 ·0.0003 · 0.003 C · Tb · Mn 0.016 · 0.001 · 0.005 <0.01 · 0.0003 ·0.003 >0.1 · 0.003 · 0.03 0.009 · 0.0003 · 0.003 C · Tb · Zn 0.017 ·0.001 · 0.005 <0.01 · 0.0003 · 0.003 >0.1 · 0.003 · 0.03 0.011 · 0.0003· 0.003 E · Ny · Cu 0.025 · 0.001 · 0.007 >0.1 · 0.003 · 0.03 >0.1 ·0.003 · 0.03 >0.1 · 0.003 · 0.03 E · Ny · Mn 0.024 · 0.001 · 0.007 >0.1· 0.003 · 0.03 0.088 · 0.003 · 0.027 >0.1 · 0.003 · 0.03 E · Ny · Zn0.022 · 0.001 · 0.007 >0.1 · 0.003 · 0.03 0.057 · 0.002 · 0.017 >0.1 ·0.003 · 0.03 C · Ny · Mn 0.035 · 0.001 · 0.010 0.053 · 0.002 ·0.016 >0.1 · 0.003 · 0.03 0.040 · 0.001 · 0.012 C · Ny · Zn 0.028 ·0.001 · 0.008 0.039 · 0.001 · 0.012 >0.1 · 0.003 · 0.03 0.039 · 0.001 ·0.012 E · PM · Cu 0.025 · 0.001 · 0.008 0.059 · 0.002 · 0.018 0.025 ·0.001 · 0.008 >0.1 · 0.003 · 0.03 E · PM · Mn 0.020 · 0.001 · 0.0060.051 · 0.002 · 0.015 0.025 · 0.001 · 0.007 >0.1 · 0.003 · 0.03 E · PM ·Zn 0.017 · 0.001 · 0.005 0.058 · 0.002 · 0.017 0.025 · 0.001 ·0.007 >0.1 · 0.003 · 0.03 C · PM · Cu 0.040 · 0.001 · 0.012 0.052 ·0.002 · 0.016 0.025 · 0.001 · 0.007 0.055 · 0.002 · 0.016 C · PM · Mn0.027 · 0.001 · 0.008 0.075 · 0.002 · 0.022 0.028 · 0.001 · 0.009 0.046· 0.001 · 0.014 C · PM · Zn 0.023 · 0.001 · 0.007 0.107 · 0.003 · 0.0320.028 · 0.001 · 0.008 0.045 · 0.001 · 0.014 G · INH · Cu 0.045 · 0.001 ·0.013 0.035 · 0.001 · 0.011 0.078 · 0.002 · 0.023 >0.1 · 0.003 · 0.03 G· INH · Mn 0.032 · 0.001 · 0.010 0.026 · 0.001 · 0.008 0.049 · 0.001 ·0.015 >0.1 · 0.003 · 0.03 G · INH · Zn 0.036 · 0.001 · 0.011 0.019 ·0.001 · 0.006 0.062 · 0.002 · 0.019 >0.1 · 0.003 · 0.03 CC · INH ·Cu >0.1 · 0.003 · 0.03 >0.1 · 0.003 · 0.03 >0.1 · 0.003 · 0.03 >0.1 ·0.003 · 0.03 CC · INH · Mn >0.1 · 0.003 · 0.03 >0.1 · 0.003 · 0.03 >0.1· 0.003 · 0.03 >0.1 · 0.003 · 0.03 CC · INH · Zn >0.1 · 0.003 · 0.030.029 · 0.001 · 0.009 >0.1 · 0.003 · 0.03 >0.1 · 0.003 · 0.03 P. g.,Porphyromonas gingivalis; UA159, Streptococcus mutans; P. a.,Pseudomonas aeruginosa; S. a., Staphylococcus aureus IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 8 Antibacterial effects of norvel regimens containing rifampin andstreptomycin. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E· Rf · Cu 0.0008 · 0.0002 · 0.0002 0.7 × 10⁻⁴ · 0.2 × 10⁻⁴ · 0.039 ·0.012 · 0.012 0.0005 · 0.0001 · 0.2 × 10⁻⁴ 0.0001 E · Rf · Mn 0.0005 ·0.0001 · 0.0001 0.4 × 10⁻⁴ · 0.1 × 10⁻⁴ · 0.034 · 0.01 · 0.01 0.0003 ·0.0001 · 0.1 × 10⁻⁴ 0.0001 E · Rf · Zn 0.0006 · 0.0002 · 0.0002 0.0002 ·0.0001 · 0.032 · 0.01 · 0.01 0.0003 · 0.0001 · 0.0001 0.0001 C · Rf · Cu0.0004 · 0.0001 · 0.0001 0.4 × 10⁻⁴ · 10⁻⁵ · 10⁻⁵ 0.028 · 0.009 · 0.0090.52 × 10⁻⁴ · 0.16 × 10⁻⁴ · 0.16 × 10⁻⁴ C · Rf · Mn 0.0004 · 0.0001 ·0.0001 0.4 × 10⁻⁴ · 10⁻⁵ · 10⁻⁵ 0.043 · 0.013 · 0.013 0.57 × 10⁻⁴ · 0.17× 10⁻⁴ · 0.17 × 10⁻⁴ C · Rf · Zn 0.0004 · 0.0001 · 0.0001 0.4 × 10⁻⁴ ·10⁻⁵ · 10⁻⁵ 0.030 · 0.009 · 0.009 0.52 × 10⁻⁴ · 0.16 × 10⁻⁴ · 0.16 ×10⁻⁴ G · Rf · Cu 0.001 · 0.0002 · 0.0002 0.0005 · 0.0001 · 0.0001 0.101· 0.015 · 0.015 0.0005 · 0.0001 · 0.0001 G · Rf · Mn 0.001 · 0.0002 ·0.0002 0.0005 · 0.0001 · 0.0001 0.062 · 0.009 · 0.009 0.0006 · 0.0001 ·0.0001 G · Rf · Zn 0.001 · 0.0002 · 0.0002 0.0004 · 0.0001 · 0.00010.066 · 0.01 · 0.01 0.0005 · 0.0001 · 0.0001 CC · Rf · Cu 0.0005 ·0.0001 · 0.0001 0.4 × 10⁻⁴ · 10⁻⁵ · 10⁻⁵ 0.053 · 0.016 · 0.016 0.48 ×10⁻⁴ · 0.14 × 10⁻⁴ · 0.14 × 10⁻⁴ CC · Rf · Mn 0.0004 · 0.0001 · 0.00010.4 × 10⁻⁴ · 10⁻⁵ · 10⁻⁵ 0.050 · 0.015 · 0.015 0.78 × 10⁻⁴ · 0.23 × 10⁻⁴· 0.23 × 10⁻⁴ CC · Rf · Zn 0.0004 · 0.0001 · 0.0001 0.4 × 10⁻⁴ · 10⁻⁵ ·10⁻⁵ 0.053 · 0.016 · 0.016 0.47 × 10⁻⁴ · 0.14 × 10⁻⁴ · 0.14 × 10⁻⁴ E ·St · Cu 0.020 · 0.006 · 0.006 0.035 · 0.011 · 0.011 0.018 · 0.005 ·0.005 0.032 · 0.010 · 0.010 E · St · Mn 0.016 · 0.005 · 0.005 0.038 ·0.011 · 0.011 0.022 · 0.006 · 0.006 0.047 · 0.014 · 0.014 E · St · Zn0.017 · 0.005 · 0.005 0.041 · 0.012 · 0.012 0.026 · 0.008 · 0.008 0.030· 0.009 · 0.009 C · St · Cu 0.016 · 0.005 · 0.005 0.017 · 0.005 · 0.0050.028 · 0.009 · 0.009 0.005 · 0.001 · 0.001 C · St · Mn 0.015 · 0.005 ·0.005 0.029 · 0.009 · 0.009 0.032 · 0.010 · 0.010 0.025 · 0.008 · 0.008C · St · Zn 0.016 · 0.005 · 0.005 0.022 · 0.007 · 0.007 0.031 · 0.010 ·0.010 0.032 · 0.010 · 0.010 G · St · Cu 0.027 · 0.004 · 0.004 0.083 ·0.012 · 0.012 0.063 · 0.010 · 0.010 0.089 · 0.013 · 0.013 G · St · Mn0.021 · 0.003 · 0.003 0.082 · 0.012 · 0.012 0.047 · 0.007 · 0.007 0.063· 0.010 · 0.010 G · St · Zn 0.024 · 0.004 · 0.004 0.052 · 0.008 · 0.0080.047 · 0.007 · 0.007 0.078 · 0.012 · 0.012 CC · St · 0.020 · 0.006 ·0.006 0.042 · 0.013 · 0.013 0.022 · 0.007 · 0.007 0.034 · 0.010 · 0.010Cu CC · St · 0.015 · 0.005 · 0.005 0.041 · 0.013 · 0.013 0.027 · 0.008 ·0.008 0.035 · 0.011 · 0.011 Mn CC · St · Zn 0.012 · 0.004 · 0.004 0.037· 0.011 · 0.011 0.030 · 0.009 · 0.009 0.035 · 0.011 · 0.011 P. g.,Porphyromonas gingivalis; UA159, Streptococcus mutans; P. a.,Pseudomonas aeruginosa; S. a., Staphylococcus aureus IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 9 Antibacterial effects of novel regimens containing polypeptides.IC₅₀ (mg/ml · mg/ml · mg/ml) Drugs P. g. UA159 P. a. S. a. E · Q · PR0.01 · 0.00001 · 0.001 0.254 · 0.0003 · 0.025 0.073 · 0.0001 · >0.3 ·0.0003 · 0.03 0.007 E · F · PR 0.004 · 0.0004 · 0.0004 0.268 · 0.027 ·0.027 0.090 · 0.009 · 0.009 >0.3 · 0.03 · 0.03 E · R · PR 0.007 · 0.0001· 0.0007 0.128 · 0.001 · 0.013 0.089 · 0.001 · 0.009 >0.3 · 0.003 · 0.03E · Q · Pro 0.008 · 0.00001 · 0.0008 0.116 · 0.0001 · 0.012 0.080 ·0.0001 · 0.008 >0.3 · 0.0003 · 0.03 E · F · Pro 0.007 · 0.0007 · 0.00070.092 · 0.009 · 0.009 0.076 · 0.008 · 0.008 >0.3 · 0.03 · 0.03 E · R ·Pro 0.008 · 0.0001 · 0.0008 0.107 · 0.001 · 0.011 0.076 · 0.001 ·0.008 >0.3 · 0.003 · 0.03 E · Q · PK84 0.006 · 0.00001 · 0.0006 0.198 ·0.0002 · 0.020 0.112 · 0.0001 · 0.011 >0.3 · 0.0003 · 0.03 E · F · PK840.003 · 0.0003 · 0.0003 0.152 · 0.015 · 0.015 0.104 · 0.010 · 0.010 >0.3· 0.03 · 0.03 E · R · PK84 0.004 · 0.00004 · 0.0004 0.124 · 0.0012 ·0.012 0.084 · 0.0008 · 0.008 >0.3 · 0.003 · 0.03 E · Q · PK37 0.006 ·0.00001 · 0.0006 0.130 · 0.0001 · 0.013 0.088 · 0.0001 · 0.009 >0.3 ·0.0003 · 0.03 E · F · PK37 0.012 · 0.0012 · 0.0012 0.148 · 0.015 · 0.0150.087 · 0.009 · 0.009 >0.3 · 0.03 · 0.03 E · R · PK37 0.008 · 0.0001 ·0.0008 0.101 · 0.001 · 0.010 0.080 · 0.001 · 0.008 >0.3 · 0.003 · 0.03 E· Q · RF 0.016 · 0.0001 · 0.003 0.089 · 0.0003 · 0.015 0.042 · 0.0001 ·0.007 0.040 · 0.0001 · 0.007 E · F · RF 0.016 · 0.005 · 0.003 0.081 ·0.024 · 0.014 0.049 · 0.015 · 0.008 0.042 · 0.013 · 0.007 E · R · RF0.010 · 0.001 · 0.002 0.024 · 0.001 · 0.004 0.066 · 0.003 · 0.011 0.046· 0.002 · 0.008 E · Q · NTX 0.023 · 0.0001 · 0.0007 >0.1 · 0.0003 ·0.003 0.077 · 0.0002 · 0.002 >0.1 · 0.0003 · 0.003 E · F · NTX 0.019 ·0.0058 · 0.0006 >0.1 · 0.03 · 0.003 0.074 · 0.022 · 0.002 >0.1 · 0.03 ·0.003 E · R · NTX 0.024 · 0.0012 · 0.0007 0.046 · 0.0023 · 0.079 · 0.004· 0.002 >0.1 · 0.005 · 0.003 0.0014 E · Q · PLA2 0.022 · 0.0001 ·0.0007 >0.1 · 0.0003 · 0.003 0.080 · 0.0002 · 0.002 >0.1 · 0.0003 ·0.003 E · F · PLA2 0.021 · 0.0064 · 0.0006 >0.1 · 0.03 · 0.003 0.094 ·0.028 · 0.003 >0.1 · 0.03 · 0.003 E · R · PLA2 0.017 · 0.0009 · 0.00050.057 · 0.0028 · 0.122 · 0.006 · 0.004 >0.1 · 0.005 · 0.003 0.0017 E · Q· CTX14 0.019 · 0.0001 · 0.0006 0.116 · 0.0003 · 0.094 · 0.0003 ·0.003 >0.1 · 0.0003 · 0.003 0.0035 E · F · CTX14 0.015 · 0.0044 ·0.0004 >0.1 · 0.03 · 0.003 0.083 · 0.025 · 0.002 >0.1 · 0.03 · 0.003 E ·R · CTX14 0.018 · 0.0009 · 0.0005 0.041 · 0.002 · 0.001 0.085 · 0.004 ·0.003 >0.1 · 0.005 · 0.003 E · Q · α-BuTx 0.021 · 0.0001 · 0.0006 >0.1 ·0.0003 · 0.003 0.081 · 0.0002 · 0.002 >0.1 · 0.0003 · 0.003 E · F ·α-BuTx 0.021 · 0.0062 · 0.0006 0.119 · 0.036 · 0.004 0.070 · 0.021 ·0.002 >0.1 · 0.03 · 0.003 E · R · α-BuTx 0.016 · 0.0008 · 0.0005 0.042 ·0.002 · 0.001 0.075 · 0.004 · 0.002 >0.1 · 0.005 · 0.003 P. g.,Porphyromonas gingivalis; UA159, Streptococcus mutans; P. a.,Pseudomonas aeruginosa; S. a., Staphylococcus aureus IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 10 Antibacterial effects of novel regimens containingpolypeptides. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E· PR · Cu 0.025 · 0.008 · 0.008 0.067 · 0.020 · 0.020 0.061 · 0.018 ·0.018 >0.1 · 0.03 · 0.03 E · PR · Mn 0.019 · 0.006 · 0.006 >0.1 · 0.03 ·0.03 0.066 · 0.020 · 0.020 >0.1 · 0.03 · 0.03 E · PR · Zn 0.022 · 0.007· 0.007 >0.1 · 0.03 · 0.03 0.054 · 0.016 · 0.016 >0.1 · 0.03 · 0.03 E ·Pro · Cu 0.020 · 0.006 · 0.006 >0.1 · 0.03 · 0.03 0.050 · 0.015 ·0.015 >0.1 · 0.03 · 0.03 E · Pro · Mn 0.016 · 0.005 · 0.005 >0.1 · 0.03· 0.03 0.055 · 0.016 · 0.016 >0.1 · 0.03 · 0.03 E · Pro · Zn 0.018 ·0.005 · 0.005 >0.1 · 0.03 · 0.03 0.045 · 0.014 · 0.014 >0.1 · 0.03 ·0.03 E · RF · Cu 0.034 · 0.010 · 0.010 >0.1 · 0.03 · 0.03 0.103 · 0.031· 0.031 >0.1 · 0.03 · 0.03 E · RF · Mn 0.027 · 0.008 · 0.008 >0.1 · 0.03· 0.03 0.063 · 0.019 · 0.019 >0.1 · 0.03 · 0.03 E · RF · Zn 0.024 ·0.007 · 0.007 >0.1 · 0.03 · 0.03 0.060 · 0.018 · 0.018 >0.1 · 0.03 ·0.03 E · PK37 · Cu 0.025 · 0.008 · 0.008 >0.1 · 0.03 · 0.03 >0.1 · 0.03· 0.03 >0.1 · 0.03 · 0.03 E · PK37 · Mn 0.018 · 0.005 · 0.005 >0.1 ·0.03 · 0.03 0.083 · 0.025 · 0.025 >0.1 · 0.03 · 0.03 E · PK37 · Zn 0.018· 0.005 · 0.005 >0.1 · 0.03 · 0.03 0.078 · 0.023 · 0.023 >0.1 · 0.03 ·0.03 E · CTX14 · Cu 0.031 · 0.001 · 0.009 0.057 · 0.002 · 0.017 0.082 ·0.002 · 0.025 >0.1 · 0.003 · 0.03 E · CTX14 · Mn 0.024 · 0.001 ·0.007 >0.1 · 0.003 · 0.03 0.063 · 0.002 · 0.019 >0.1 · 0.003 · 0.03 E ·CTX14 · Zn 0.024 · 0.001 · 0.007 >0.1 · 0.003 · 0.03 0.049 · 0.001 ·0.015 >0.1 · 0.003 · 0.03 E · α-BuTx · Cu 0.024 · 0.001 · 0.007 0.068 ·0.002 · 0.020 0.081 · 0.002 · 0.024 >0.1 · 0.003 · 0.03 E · α-BuTx · Mn0.022 · 0.001 · 0.007 >0.1 · 0.003 · 0.03 0.070 · 0.002 · 0.021 >0.1 ·0.003 · 0.03 E · α-BuTx · Zn 0.020 · 0.001 · 0.006 >0.1 · 0.003 · 0.030.050 · 0.002 · 0.015 >0.1 · 0.003 · 0.03 E · PLA2 · Cu 0.022 · 0.001 ·0.007 0.053 · 0.002 · 0.016 >0.1 · 0.003 · 0.03 >0.1 · 0.003 · 0.03 E ·PLA2 · Mn 0.019 · 0.001 · 0.006 >0.1 · 0.003 · 0.03 0.092 · 0.003 ·0.027 >0.1 · 0.003 · 0.03 E · PLA2 · Zn 0.019 · 0.001 · 0.006 >0.1 ·0.003 · 0.03 0.071 · 0.002 · 0.021 >0.1 · 0.003 · 0.03 E · ML · Cu 0.025· 0.001 · 0.007 0.083 · 0.002 · 0.025 >0.1 · 0.003 · 0.03 >0.1 · 0.003 ·0.03 E · ML · Mn 0.018 · 0.001 · 0.005 >0.1 · 0.003 · 0.03 0.088 · 0.003· 0.026 >0.1 · 0.003 · 0.03 E · ML · Zn 0.019 · 0.001 · 0.006 0.087 ·0.003 · 0.026 0.097 · 0.003 · 0.029 >0.1 · 0.003 · 0.03 P. g.,Porphyromonas gingivalis; UA159, Streptococcus mutans; P. a.,Pseudomonas aeruginosa; S. a., Staphylococcus aureus IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 11 Antibacterial effects of memantine (Mem) and metformin (MF)regimens. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E ·Mem · Cu* 0.028 · 0.028 · 0.028 0.276 · 0.276 · 0.276 0.073 · 0.073 ·0.073 0.089 · 0.089 · 0.089 E · Mem · Ag* 0.014 · 0.014 · 0.009 0.325 ·0.325 · 0.218 0.066 · 0.066 · 0.066 >0.1 · 0.1 · 0.1 E · Mem · Mn 0.071· 0.071 · 0.071 0.146 · 0.146 · 0.146 0.118 · 0.118 · 0.118 0.060 ·0.060 · 0.060 E · Mem · VO₄ 0.022 · 0.022 · 0.022 >0.1 · 0.1 · 0.1 >0.1· 0.1 · 0.1 >0.1 · 0.1 · 0.1 E · Mem · Zn* 0.065 · 0.065 · 0.065 0.092 ·0.092 · 0.092 0.071 · 0.071 · 0.071 >0.1 · 0.1 · 0.1 E · Mem · Sr 0.075· 0.075 · 0.226 0.110 · 0.110 · 0.329 0.155 · 0.155 · 0.464 >0.1 · 0.1 ·0.3 C · Mem · Cu 0.062 · 0.062 · 0.019 0.036 · 0.011 · 0.011 0.060 ·0.018 · 0.018 C · Mem · Ag 0.032 · 0.032 · 0.003 C · Mem · Mn 0.037 ·0.037 · 0.011 0.090 · 0.027 · 0.027 0.049 · 0.015 · 0.015 C · Mem · VO₄0.048 · 0.048 · 0.014 C · Mem · Zn 0.047 · 0.047 · 0.014 C · Mem · Sr0.041 · 0.041 · 0.041 E · MF · Cu* 0.050 · 0.015 · 0.050 0.094 · 0.094 ·0.094 0.623 · 0.187 · 0.623 >0.1 · 0.03 · 0.1 E · MF · Se* 0.040 · 0.012· 0.040 0.042 · 0.042 · 0.042 0.090 · 0.027 · 0.090 >0.1 · 0.03 · 0.1 E· MF · Mn* 0.060 · 0.018 · 0.060 >0.1 · 0.03 · 0.1 >0.1 · 0.03 · 0.10.044 · 0.013 · 0.044 E · MF · VO₄* 0.037 · 0.011 · 0.037 0.259 · 0.078· 0.259 >0.1 · 0.03 · 0.1 >0.1 · 0.03 · 0.1 E · MF · Zn* 0.066 · 0.020 ·0.066 0.259 · 0.078 · 0.259 >0.1 · 0.03 · 0.1 >0.1 · 0.03 · 0.1 E · MF ·Sr* 0.097 · 0.029 · 0.292 >0.1 · 0.03 · 0.3 >0.1 · 0.03 · 0.3 >0.1 ·0.03 · 0.3 C · MF · Cu >0.03 · 0.03 · 0.1 0.046 · 0.046 · 0.014 0.042 ·0.042 · 0.013 C · MF · Ag 0.008 · 0.008 · 0.017 C · MF · Mn >0.03 · 0.03· 0.1 0.066 · 0.066 · 0.020 0.047 · 0.047 · 0.014 C · MF · VO₄ >0.03 ·0.03 · 0.1 C · MF · Zn* >0.03 · 0.03 · 0.1 C · MF · Sr >0.03 · 0.03 ·0.3 G · Mem · Cu* 0.032 · 0.005 · 0.005 0.022 · 0.003 · 0.003 0.205 ·0.031 · 0.031 >0.2 · 0.03 · 0.03 G · Mem · Ag* 0.023 · 0.003 · 0.0010.013 · 0.002 · 0.001 0.103 · 0.015 · 0.005 >0.2 · 0.03 · 0.01 G · Mem ·Mn* 0.030 · 0.005 · 0.005 0.061 · 0.009 · 0.009 0.112 · 0.017 · 0.0170.095 · 0.014 · 0.014 G · Mem · VO₄* 0.046 · 0.007 · 0.007 0.072 · 0.011· 0.011 >0.2 · 0.03 · 0.03 >0.2 · 0.03 · 0.03 G · Mem · Zn* 0.031 ·0.005 · 0.005 0.051 · 0.008 · 0.008 0.118 · 0.018 · 0.018 >0.2 · 0.03 ·0.03 G · Mem · Sr* 0.036 · 0.005 · 0.018 0.059 · 0.009 · 0.029 0.114 ·0.017 · 0.057 >0.2 · 0.03 · 0.1 G · MF · Cu* 0.042 · 0.021 · 0.006 0.146· 0.073 · 0.022 0.138 · 0.070 · 0.021 >0.2 · 0.1 · 0.03 G · MF · Ag0.025 · 0.012 · 0.001 >0.2 · 0.1 · 0.01 0.076 · 0.038 · 0.004 >0.2 · 0.1· 0.01 G · MF · Mn* 0.024 · 0.012 · 0.004 >0.2 · 0.1 · 0.03 0.065 ·0.032 · 0.010 0.264 · 0.132 · 0.040 G · MF · VO4 0.039 · 0.019 ·0.006 >0.2 · 0.1 · 0.03 >0.2 · 0.1 · 0.03 >0.2 · 0.1 · 0.03 G · MF · Zn*0.032 · 0.016 · 0.005 0.147 · 0.073 · 0.022 0.104 · 0.052 · 0.016 >0.2 ·0.1 · 0.03 G · MF · Sr 0.027 · 0.013 · 0.013 >0.2 · 0.1 · 0.1 0.077 ·0.038 · 0.038 >0.2 · 0.1 · 0.1 P. g., Porphyromonas gingivalis; UA159,Streptococcus mutans; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus. IC₅₀, concentrations of 50% inhibition onbacterial proliferation. *The drug combinations listed in this table atconcentrations of 3 to 10 times higher than the listed IC₅₀ have noinhibition on the proliferation of the cultured Lactobacillus reuteri

TABLE 12 Antibacterial effects of norvel regimens containing naturalproducts. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a. E · Bb· Cu 0.020 · 0.006 · 0.006 0.035 · 0.011 · 0.011 0.080 · 0.024 ·0.024 >0.1 · 0.03 · 0.03 E · Bb · Mn 0.018 · 0.005 · 0.005 0.037 · 0.011· 0.011 0.063 · 0.019 · 0.019 >0.1 · 0.03 · 0.03 E · Bb · Zn 0.017 ·0.005 · 0.005 0.039 · 0.012 · 0.012 0.064 · 0.019 · 0.019 >0.1 · 0.03 ·0.03 C · Bb · Cu 0.069 · 0.021 · 0.021 0.036 · 0.011 · 0.011 >0.1 · 0.03· 0.03 0.031 · 0.009 · 0.009 C · Bb · Mn 0.039 · 0.012 · 0.012 0.054 ·0.016 · 0.016 >0.1 · 0.03 · 0.03 0.036 · 0.011 · 0.011 C · Bb · Zn 0.034· 0.010 · 0.010 0.044 · 0.013 · 0.013 >0.1 · 0.03 · 0.03 0.032 · 0.010 ·0.010 G · Bb · Mn 0.028 · 0.004 · 0.004 0.091 · 0.014 · 0.014 0.238 ·0.036 · 0.036 >0.2 · 0.03 · 0.03 G · Bb · Zn 0.013 · 0.002 · 0.002 0.076· 0.011 · 0.011 0.116 · 0.017 · 0.017 >0.2 · 0.03 · 0.03 E · Qc · Cu0.020 · 0.006 · 0.006 0.069 · 0.021 · 0.021 0.084 · 0.023 · 0.023 >0.1 ·0.03 · 0.03 E · Qc · Mn 0.015 · 0.005 · 0.005 0.087 · 0.026 · 0.0260.054 · 0.016 · 0.016 >0.1 · 0.03 · 0.03 E · Qc · Zn 0.015 · 0.004 ·0.004 >0.1 · 0.03 · 0.03 0.063 · 0.019 · 0.019 >0.1 · 0.03 · 0.03 C · Qc· Cu 0.037 · 0.011 · 0.011 0.149 · 0.045 · 0.045 >0.1 · 0.03 · 0.03 >0.1· 0.03 · 0.03 C · Qc · Mn 0.027 · 0.008 · 0.008 0.076 · 0.023 ·0.023 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 C · Qc · Zn 0.023 · 0.007 ·0.007 0.086 · 0.026 · 0.026 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 G · Qc· Mn 0.026 · 0.004 · 0.004 0.117 · 0.018 · 0.018 0.131 · 0.020 ·0.020 >0.2 · 0.03 · 0.03 G · Qc · Zn 0.018 · 0.003 · 0.003 0.078 · 0.012· 0.012 0.119 · 0.018 · 0.018 >0.2 · 0.03 · 0.03 E · TMP · Cu 0.017 ·0.005 · 0.005 0.094 · 0.028 · 0.028 0.053 · 0.016 · 0.016 >0.1 · 0.03 ·0.03 E · TMP · Mn 0.013 · 0.004 · 0.004 >0.1 · 0.03 · 0.03 0.054 · 0.016· 0.016 >0.1 · 0.03 · 0.03 E · TMP · Zn 0.014 · 0.004 · 0.004 >0.1 ·0.03 · 0.03 0.038 · 0.011 · 0.011 >0.1 · 0.03 · 0.03 C · TMP · Cu 0.015· 0.005 · 0.005 0.045 · 0.013 · 0.013 0.063 · 0.019 · 0.019 0.048 ·0.014 · 0.014 C · TMP · Mn 0.010 · 0.003 · 0.003 0.037 · 0.011 · 0.0110.042 · 0.013 · 0.013 0.059 · 0.018 · 0.018 C · TMP · Zn 0.011 · 0.003 ·0.003 0.029 · 0.009 · 0.009 0.051 · 0.015 · 0.015 0.048 · 0.014 · 0.014G · TMP · Cu 0.026 · 0.008 · 0.008 >0.1 · 0.03 · 0.03 >0.1 · 0.03 ·0.03 >0.1 · 0.03 · 0.03 G · TMP · Mn 0.017 · 0.005 · 0.005 0.052 · 0.016· 0.016 >0.1 · 0.03 · 0.03 >0.1 · 0.03 · 0.03 G · TMP · Zn 0.017 · 0.005· 0.005 0.024 · 0.007 · 0.007 0.083 · 0.025 · 0.025 >0.1 · 0.03 · 0.03CC · TMP · Cu 0.030 · 0.009 · 0.009 >0.1 · 0.03 · 0.03 >0.1 · 0.03 ·0.03 >0.1 · 0.03 · 0.03 CC · TMP · Mn 0.017 · 0.005 · 0.005 >0.1 · 0.03· 0.03 >0.1 · 0.03 · 0.03 0.100 · 0.030 · 0.030 CC · TMP · Zn 0.025 ·0.007 · 0.007 0.087 · 0.026 · 0.026 >0.1 · 0.03 · 0.03 0.074 · 0.022 ·0.022 E · NDGA · Cu 0.015 · 0.004 · 0.004 0.037 · 0.011 · 0.011 0.040 ·0.012 · 0.012 >0.1 · 0.03 · 0.03 E · NDGA · Mn 0.014 · 0.004 · 0.0040.033 · 0.010 · 0.010 0.040 · 0.012 · 0.012 >0.1 · 0.03 · 0.03 E · NDGA· Zn 0.014 · 0.004 · 0.004 0.033 · 0.010 · 0.010 0.039 · 0.012 ·0.012 >0.1 · 0.03 · 0.03 C · NDGA · Cu 0.018 · 0.005 · 0.005 0.030 ·0.009 · 0.009 0.131 · 0.039 · 0.039 0.030 · 0.009 · 0.009 C · NDGA · Mn0.012 · 0.004 · 0.004 0.032 · 0.010 · 0.010 0.049 · 0.015 · 0.015 0.058· 0.017 · 0.017 C · NDGA · Zn 0.011 · 0.003 · 0.003 0.035 · 0.010 ·0.010 0.051 · 0.015 · 0.015 0.049 · 0.015 · 0.015 G · NDGA · Cu 0.022 ·0.007 · 0.007 <0.01 · 0.003 · 0.003 >0.1 · 0.03 · 0.03 >0.1 · 0.03 ·0.03 G · NDGA · Mn 0.019 · 0.006 · 0.006 0.020 · 0.006 · 0.006 0.070 ·0.021 · 0.021 >0.1 · 0.03 · 0.03 G · NDGA · Zn 0.018 · 0.005 · 0.0050.020 · 0.006 · 0.006 0.074 · 0.022 · 0.022 >0.1 · 0.03 · 0.03 CC · NDGA· Cu 0.034 · 0.010 · 0.010 <0.01 · 0.003 · 0.003 >0.1 · 0.03 · 0.030.053 · 0.016 · 0.016 CC · NDGA · Mn 0.021 · 0.006 · 0.006 0.038 · 0.011· 0.011 >0.1 · 0.03 · 0.03 >0.01 · 0.003 · 0.003 CC · NDGA · Zn 0.025 ·0.008 · 0.008 0.031 · 0.009 · 0.009 >0.1 · 0.03 · 0.03 0.043 · 0.013 ·0.013 P. g., Porphyromonas gingivalis; UA159, Streptococcus mutans; P.a., Pseudomonas aeruginosa; S. a., Staphylococcus aureus. IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 13 Antibacterial effects of novel regimens containing etidronate(Eti), glibenclamide (Gbc) or 3,4-diaminopysidine (3,4-DAP). IC₅₀ (mg/ml· mg/ml · mM) Drugs P. g. UA159 P. a. S. a. A. E · Eti · Cu 0.048 ·0.143 · 0.048 0.080 · 0.239 · 0.080 >0.1 · 0.1 · 0.1 0.027 · 0.082 ·0.027 E · Eti · Ag* 0.019 · 0.057 · 0.019 0.145 · 0.436 · 0.044 E · Eti· Mn 0.037 · 0.112 · 0.037 0.632 · 1.895 · 0.632 >0.1 · 0.1 · 0.1 0.022· 0.067 · 0.022 E · Eti · VO₄ 0.051 · 0.152 · 0.051 0.087 · 0.260 ·0.087 >0.1 · 0.1 · 0.1 0.028 · 0.085 · 0.028 E · Eti · Zn 0.042 · 0.126· 0.042 0.169 · 0.508 · 0.169 >0.1 · 0.1 · 0.1 0.036 · 0.107 · 0.036 E ·Eti · Sr 0.04 · 0.128 · 0.13 2.81 · 8.443 · 8.44 >0.1 · 0.1 · 0.3 0.02 ·0.069 · 0.07 C · Eti · Cu 0.037 · 0.110 · 0.011 >0.1 · 0.3 · 0.03 0.028· 0.083 · 0.008 C · Eti · Ag 0.031 · 0.092 · 0.003 >0.1 · 0.3 · 0.010.026 · 0.079 · 0.008 C · Eti · Mn 0.032 · 0.095 · 0.009 >0.1 · 0.3 ·0.03 0.022 · 0.065 · 0.007 C · Eti · VO₄ 0.038 · 0.113 · 0.011 >0.1 ·0.3 · 0.03 0.044 · 0.131 · 0.013 C · Eti · Zn 0.038 · 0.115 · 0.012 >0.1· 0.3 · 0.03 0.026 · 0.078 · 0.008 C · Eti · Sr 0.037 · 0.112 ·0.037 >0.1 · 0.3 · 0.1 0.029 · 0.088 · 0.029 G · Eti · Cu* 0.051 · 0.076· 0.008 0.065 · 0.098 · 0.010 >0.2 · 0.3 · 0.03 >0.2 · 0.3 · 0.03 G ·Eti · Ag* 0.030 · 0.045 · 0.001 0.041 · 0.062 · 0.002 >0.2 · 0.3 ·0.01 >0.2 · 0.3 · 0.01 G · Eti · Mn* 0.041 · 0.061 · 0.006 0.047 · 0.071· 0.007 >0.2 · 0.3 · 0.03 >0.2 · 0.3 · 0.03 G · Eti · VO₄* 0.045 · 0.067· 0.007 0.057 · 0.086 · 0.009 >0.2 · 0.3 · 0.03 >0.2 · 0.3 · 0.03 G ·Eti · Zn* 0.046 · 0.068 · 0.007 0.052 · 0.078 · 0.008 >0.2 · 0.3 ·0.03 >0.2 · 0.3 · 0.03 G · Eti · Sr* 0.047 · 0.070 · 0.023 0.026 · 0.040· 0.013 >0.2 · 0.3 · 0.1 >0.2 · 0.3 · 0.1 B. E · Gbc · Cu 0.038 · 2.5 ×10⁻⁴ · 0.038 >0.1 · 6.6 × 10⁻⁴ · 0.1 0.116 · 7.7 × 10⁻⁴ · 0.116 >0.1 ·6.6 × 10⁻⁴ · 0.1 E · Gbc · Se 0.039 · 2.6 × 10⁻⁴ · 0.039 0.040 · 2.7 ×10⁻⁴ · 0.04 0.098 · 6.5 × 10⁻⁴ · 0.098 >0.1 · 6.6 × 10⁻⁴ · 0.1 E · Gbc ·Mn 0.084 · 5.5 × 10⁻⁴ · 0.084 >0.1 · 6.6 × 10⁻⁴ · 0.1 0.097 · 6.4 × 10⁻⁴· 0.097 0.070 · 4.6 × 10⁻⁴ · 0.07 E · Gbc · VO₄ >0.1 · 6.6 × 10⁻⁴ ·0.1 >0.1 · 6.6 · 6 × 10⁻⁴ · 0.1 >0.1 · 6.6 × 10⁻⁴ · 0.1 >0.1 · 6.6 ×10⁻⁴ · 0.1 E · Gbc · Zn 0.074 · 4.9 × 10⁻⁴ · 0.074 >0.1 · 6.6 × 10⁻⁴ ·0.1 0.096 · 6.4 × 10⁻⁴ · 0.096 >0.1 · 6.6 × 10⁻⁴ · 0.1 E · Gbc · Sr 0.07· 4.9 × 10⁻⁴ · 0.22 >0.1 · 6.6 × 10⁻⁴ · 0.3 0.128 · 8.5 × 10⁻⁴ ·0.385 >0.1 · 6.6 × 10⁻⁴ · 0.3 E · 3,4DAP · 0.062 · 0.019 · 0.062 >0.1 ·0.03 · 0.1 0.210 · 0.063 · 0.210 >0.1 · 0.03 · 0.1 Cu E · 3,4DAP · 0.027· 0.008 · 0.027 0.022 · 0.007 · 0.022 0.220 · 0.066 · 0.220 >0.1 · 0.03· 0.1 Se E · 3,4DAP · 0.195 · 0.058 · 0.195 >0.1 · 0.03 · 0.1 >0.1 ·0.03 · 0.1 >0.1 · 0.03 · 0.1 Mn E · 3,4DAP · 0.014 · 0.004 · 0.014 >0.1· 0.03 · 0.1 >0.1 · 0.03 · 0.1 >0.1 · 0.03 · 0.1 VO₄ E · 3,4DAP · >0.1 ·0.03 · 0.1 >0.1 · 0.03 · 0.1 0.191 · 0.057 · 0.191 >0.1 · 0.03 · 0.1 ZnE · 3,4DAP · >0.1 · 0.03 · 0.3 >0.1 · 0.03 · 0.3 0.271 · 0.081 ·0.813 >0.1 · 0.03 · 0.3 Sr C. IC₅₀ (mg/ml · mg/ml · mM · mg/ml) Drugs P.g. UA159 E · Gbc · Zn · Mem 0.047 · 3.1 × 10⁻⁴ · 0.047 · 0.047 >0.075 ·5 × 10⁻⁴ · 0.075 · 0.075 E · Gbc · Sr · Mem 0.050 · 3.3 × 10⁻⁴ · 0.050 ·0.050 >0.075 · 5 × 10⁻⁴ · 0.225 · 0.075 E · Gbc · Ge · Mem 0.049 · 3.3 ×10⁻⁴ · 0.049 · 0.049 >0.075 · 5 × 10⁻⁴ · 0.025 · 0.075 E · 3,4DAP · Cu ·Mem 0.020 · 0.007 · 0.020 · 0.020 >0.075 · 0.025 · 0.075 · 0.075 E ·3,4DAP · Mn · Mem 0.023 · 0.008 · 0.023 · 0.023 >0.075 · 0.025 · 0.075 ·0.075 E · 3,4DAP · Zn · Mem 0.024 · 0.008 · 0.024 · 0.024 >0.075 · 0.025· 0.075 · 0.075 E · 3,4DAP · Sr · Mem 0.021 · 0.007 · 0.021 ·0.021 >0.075 · 0.025 · 0.225 · 0.075 E · 3,4DAP · Ge · Mem 0.018 · 0.006· 0.018 · 0.018 >0.075 · 0.025 · 0.025 · 0.075 P. g., Porphyromonasgingivalis; UA159, Streptococcus mutans; P. a., Pseudomonas aeruginosa;S. a., Staphylococcus aureus IC₅₀, concentrations of 50% inhibition onbacterial proliferation. *The drug combinations listed in this table atconcentrations of 3 to 10 times higher than the listed IC₅₀ have noinhibition on the proliferation of the cultured Lactobacillus reuteri

TABLE 14 Antibacterial effects of novel regimens cotaiming AgCl, Ge andcisplatin (Pt).. IC₅₀ (mg/ml · mg/ml · mM) Drugs P. g. UA159 P. a. S. a.A. E · Q · Ag 0.040 · 0.0001 · 0.007 >0.1 · 0.0003 · 0.021 0.017 ·0.0001 · 0.007 0.017 · 0.0001 · 0.007 E · F · Ag 0.105 · 0.031 · 0.0210.165 · 0.049 · 0.035 0.125 · 0.038 · 0.028 0.018 · 0.005 · 0.007 E · R· Ag 0.069 · 0.003 · 0.014 0.033 · 0.002 · 0.007 0.018 · 0.001 · 0.0070.023 · 0.001 · 0.007 E · Gbc · Ag 0.185 · 1.22 × 10⁻³ · 0.133 · 8.76 ×10⁻⁴ · 0.017 · 1.12 × 10⁻⁴ · >0.1 · 6.6 × 10⁻⁴ · 0.021 0.042 0.028 0.007E · 34DAP · 0.042 · 0.013 · 0.007 0.149 · 0.045 · 0.028 0.016 · 0.005 ·0.007 0.021 · 0.006 · 0.004 Ag E · Mem · Ag 0.041 · 0.041 · 0.007 0.149· 0.149 · 0.028 0.019 · 0.019 · 0.007 0.044 · 0.044 · 0.007 E · MF · Ag0.183 · 0.055 · 0.035 0.418 · 0.125 · 0.143 0.017 · 0.005 · 0.007 >0.1 ·0.03 · 0.021 E · CPZ · Ag 0.026 · 0.008 · 0.007 0.034 · 0.010 · 0.0070.017 · 0.005 · 0.007 0.024 · 0.007 · 0.007 E · Eti · Ag 0.029 · 0.086 ·0.007 0.115 · 0.344 · 0.021 0.021 · 0.064 · 0.007 0.050 · 0.151 · 0.014E · Clo · Ag 0.058 · 0.175 · 0.014 >0.1 · 0.3 · 0.021 0.186 · 0.559 ·0.042 >0.1 · 0.3 · 0.021 Ag 0.014 mM 0.035 mM 0.042 mM 0.056 mM B. E · Q· Ge 1.269 · 0.0038 · 3.81 >0.1 · 0.0003 · 0.3 E · F · Ge 0.199 · 0.060· 0.596 >0.1 · 0.03 · 0.3 E · R · Ge 0.046 · 0.002 · 0.139 >0.1 · 0.005· 0.3 F · Q · Ge >0.03 · 0.0003 · 0.3 0.815 · 0.008 · 8.15 F · R · Ge0.037 · 0.006 · 0.371 0.3 · 0.05 · 2.99 R · U · Ge 0.005 · 0.030 ·0.295 >0.005 · 0.03 · 0.3 C. E · Q · Pt 0.039 · 0.0001 · 0.012 >0.1 ·0.001 · 0.03 0.040 · 0.0001 · 0.012 0.041 · 0.0001 · 0.012 E · R · Pt0.038 · 0.002 · 0.001 0.028 · 0.004 · 0.008 0.069 · 0.003 · 0.021 0.043· 0.002 · 0.013 E · Et · Pt 0.046 · 0.0014 · 0.014 >0.1 · 0.03 · 0.03 E· Pt 0.046 · 0.015 0.154 · 0.051 R · Pt 0.005 · 0.003 Et 0.125 mg/ml >0.1 mg/ml Pt 0.069 mM  >0.1 mM P. g., Porphyromonas gingivalis; UA159,Streptococcus mutans; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus IC₅₀, concentrations of 50% inhibition onbacterial proliferation.

TABLE 15 Antibacterial effects of herbs-metallic compounds. IC₅₀ Av.Drugs (mg/ml · mg/ml · mM) Potency Potency A. Porphyromonas gingivalis E· GIM 0.023 · 0.076 3.70 · 12.42 8 E · GIM · Zn 0.022 · 0.066 · 0.0073.86 · 14.30 · 90.29 36 E · OP 0.022 · 0.022 6.86 · 13.64 9 E · OP · Zn0.019 · 0.019 · 0.006 4.47 · 15.79 · 105.33 42 T · GIM 0.055 · 0.1823.04 · 5.19 4 T · GIM · Zn 0.031 · 0.092 · 0.009 5.39 · 10.26 · 70.22 59T · OP 0.036 · 0.036 4.64 · 8.33 6 T · OP · Zn 0.032 · 0.032 · 0.0105.22 · 9.38 · 63.20 26 G · GIM 0.035 · 0.115 3.89 · 8.21 6 G · GIM · Zn0.025 · 0.075 · 0.008 5.44 · 12.59 · 79 32 G · OP 0.030 · 0.030 4.53 ·10 7 G · OP · Zn 0.025 · 0.025 · 0.008 5.44 · 12 · 79 32 B.Streptococcus mutans E · GIM 0.067 · 0.224 2.04 · 4.46 3 E · OP 0.085 ·0.085 1.61 · 3.53 3 G · GIM 0.076 · 0.254 13.16 · 3.94 9 G · OP 0.059 ·0.059 16.95 · 5.08 11 G · OP · Zn 0.052 · 0.052 · 0.016 19.23 · 5.77 ·125 50 T · GIM 0.084 · 0.280 1.48 · 3.57 3 T · GIM · Zn 0.072 · 0.217 ·0.022 1.72 · 4.61 · 90.91 32 T · OP · Zn 0.049 · 0.049 · 0.015 2.53 ·6.12 · 133.33 47 IC₅₀, concentrations of 50% inhibition on bacterialproliferation.

TABLE 16 Selective antibacterial effects of novel regimens withoutinhibition on neuroblastoma SHSY5Y cells IC₅₀ (mg/ml · mg/ml · mM)SHSY5Y P. g. UA159 E. Coli B. s. P. a. S. a. L. r. C · MF · Cu >0.03 ·0.03 · >0.03 · 0.03 · >0.1 · 0.1 · 0057 · 0024 · 0.046 · 0.046 · 0.042 ·0.213 · 0.213 · 0.1 0.1 0.03 0057 · 0024 · 0.014 0.042 · 0.064 0.0170.007 0.013 C · MF · VO₄ >0.03 · 0.03 · >0.03 · 0.03 · >0.03 · >0.03· >0.03 · 0.03 · >0.03 · 0.1 0.1 0.03 · 0.03 · 0.1 0.1 0.03 · 0.1 0.1 C· MF · Zn >0.03 · 0.03 · >0.03 · 0.03 · 0.027 · 0.049 · 0.031 · 0.061 ·0.061 · 0.030 · 0.027 · 0.027 · 0.1 0.1 0.027 · 0.049 · 0.031 · 0.0180.030 · 0.008 0.008 0.015 0.009 0.009 C · MF · Sr >0.03 · 0.03 · >0.03 ·0.03 · 0.3 0.3 E · TRZ · RuR >0.3 · 0.03 · 0.024 · 0.001 · 0.114 · 0.090· >0.3 · 0.03 · 0.047 · 0.002 · 0.143 · 0.249 · 0.008 · 0.04 0.002 0.004· 0.003 · 0.04 0.006 0.005 · 0.029 0.013 0.010 0.016 E · Eti · RuR >0.03· 0.3 · 0.04 0.0078 · 0.078 · 0.064 · 0.287 · 0.334 · 0.069 · 0.069 ·0.290 · >0.3 · 0.3 · 0.009 0.064 · 0.287 · 0.334 · 0.008 0.290 · 0.040.007 0.03 0.04 0.03 E · Mem · Zn >0.1 · 0.03 · 0.065 · 0.065 · 0.092 ·0.433 · >0.1 · 0.03 · 0.071 · 0.071 · >0.1 · >0.1 · 0.03 · 0.03 0.0650.092 · 0.130 · 0.03 0.071 0.1 · 0.1 0.03 0.092 0.130 G · CC · VO₄ >0.2· 0.1 · 0.03 0.049 · 0.025 · 0.204 · >0.2 · >0.2 · 0.1 · >0.2 · 0.1· >0.2 · >0.2 · 0.1 · 0.007 0.120 · 0.1 · 0.03 0.03 0.1 · 0.03 0.030.036 0.03 C · TRZ · RuR >0.1 · 0.01 · 0.021 · 0.002 · 0.027 · >0.1 ·0.076 · 0.030 · 0.003 · 0.038 · 0.046 · 0.005 · 0.04 0.007 0.003 · 0.01· 0.008 · 0.010 0.004 · 0.016 0.009 0.04 0.027 0.013 C · CPZ · RuR >0.1· 0.01 · 0.019 · 0.002 · 0.023 · >0.1 · 0.039 · 0.031 · 0.003 · 0.041 ·0.052 · 0.005 · 0.04 0.007 0.002 · 0.01 · 0.004 · 0.010 0.004 · 0.0190.008 0.04 0.014 0.013 C · MF · RuR >0.1 · 0.1 · 0.023 · 0.023 · 0.022· >0.1 · >0.03 · 0.040 · 0.040 · 0.039 · 0.040 · 0.040 · 0.04 0.0080.022 · 0.1 · 0.03 · 0.012 0.014 0.039 · 0.014 0.008 0.04 0.014 E · OP ·Zn >0.1 · 0.1 · 0.023 · 0.023 · >0.1 · >0.1 · >0.03 · 0.03 · >0.1 · >0.1· 0.1 · 0.03 0.007 0.1 · 0.1 · 0.01 0.1 · 0.03 0.03 0.03 0.03 G · OP ·Zn >0.1 · 0.1 · 0.022 · 0.022 · >0.1 · >0.1 · >0.1 · 0.1 · >0.1 · >0.1 ·0.1 · 0.03 0.007 0.1 · 0.1 · 0.03 0.01 · 0.03 0.03 0.03 0.03 T · OP ·Zn >0.1 · 0.1 · 0.024 · 0.024 · >0.1 · >0.1 · >0.1 · 0.1 · >0.1 · >0.1 ·0.03 0.007 0.1 · 0.1 · 0.03 0.1 · 0.1 · 0.03 0.03 0.03 0.03 G · GIM ·Zn >0.2 · 0.3 · 0.022 · 0.033 · 0.184 · >0.6 · 0.192 · 0.287 · >0.6 ·0.443 · 0.664 · 0.03 0.004 0.277 · 0.9 · 0.032 0.9 · 0.074 0.031 0.1 0.1G · CC · Zn >0.2 · 0.1 · 0.019 · 0.009 · 0.063 · >0.2 · 0.108 · 0.054 ·0.103 · 0.147 · 0.074 · 0.03 0.003 0.032 · 0.1 · 0.016 0.052 · 0.0220.010 0.03 0.015 P. g., Porphyromonas gingivalis; UA159, Streptococcusmutans; B. s., Bacillus subtilis; P. a., Pseudomonas aeruginosa; S. a.,Staphylococcus aureus, L. r., Lactobacillus reuteri. IC₅₀,concentrations of 50% inhibition on bacterial proliferation.

TABLE 17 Anti-proliferative effects of drug combinations on cancer cellsmore than on normal SG cells. IC₅₀ (mg/ml · mg/ml · mM) Potency DrugsOECM-1 cells SG cells ratio C · Mem · VO₄ 0.002 · 0.005 · 0.005 0.009 ·0.031 · 0.031 6 C · MF · VO₄ 0.001 · 0.001 · 0.002 0.015 · 0.015 · 0.05025 C · CPZ · VO₄ 0.001 · 0.001 · 0.004 0.007 · 0.007 · 0.023 6 C · Eti ·VO₄ 0.001 · 0.010 · 0.003 0.025 · 0.254 · 0.085 28 E · Eti · RuR 0.047 ·0.047 · 0.006 0.442 · 0.442 · 0.051 9 T · TRZ · RuR 0.031 · 0.009 ·0.010 0.633 · 0.199 · 0.231 22 OECM-1, oral squamons carcinoma cells;SG, normal oral keratinocytes. IC₅₀, concentrations of 50% inhibition oncell proliferation.

What is claimed is:
 1. A pharmaceutical composition(PTM) for use in antimicrobial effects against pathogen and/or for use in prevention and therapy of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndromes, periodontitis, dental caries, osteoporosis, cancers and/or chronic pain, comprising a polyphenols(P), a clinical drugs with selective targets(T) and a metal ions(M).
 2. The pharmaceutical composition of claim 1, wherein the polyphenols is at least one selected from the group comprising tea polyphenols, curcumin, EGCG, theaflavin, apigenin, berberin, quercetin, tannin, catechin, chlorogenic acid, isoflavone, anthocyanidin, cocoa polyphenols, citrin, tetramethylpyrazine, nordihydroguaiaretic acid, flavonoid and resveratrol etc.
 3. The pharmaceutical composition of claim 1, wherein the clinical drug with selective target is at least one selected from the group comprising receptor agonists or antagonists, ion channel modulators, membrane ion transporters, mitochondrial functional modulators, immune modulators and antibiotics.
 4. The pharmaceutical composition of claim 1, wherein the clinical drug with selective target is at least one selected from the group comprising NaF, memantine, metformin, thioridazine, chlorpromazine, tobramycin, rifampin, strepotomycin, isoniazide, verapamil, diltiazem, dithiothretol, dibucaine, digitonin, polymycin B, cisplatin, dequalinium, 4-hexylresorcinol, ursodeoxycholic acid, etidronate, glibenclamide and 3,4-diaminopyridine.
 5. The pharmaceutical composition of claim 1, wherein the metal ions is at least one selected from the group comprising Cu²⁺, Mn²⁺, VO₄ ²⁺, Zn²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, Ge132 and RuR(Ruthenium red).
 6. The pharmaceutical composition of claim 1, wherein the antimicrobial pathogen is at least one selected from the group comprising Porphyromonas gingivalis, Streptococcus mutans, E. coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphytococcus aureus, MRSA and Mycobacterium tuberculosis.
 7. The pharmaceutical composition of claim 1, wherein the proportion between the concentration of the polyphenols and the clinical drug with selective target is 1:0.1-3.
 8. The pharmaceutical composition of claim 1, wherein an interaction between the polyphenols, the clinical drug with selective target and the metal ions leading to synergistic effects.
 9. A method for use in antimicrobial pathogens and/or for use in prevention and therapy of infectious diseases, neurodegenerative diseases, dementia, diabetes, obesity, metabolic syndromes, periodontitis, dental caries, osteoporosis, cancers and/or chronic pain, the method comprising administering to a subject in need thereof a polyphenols, a clinical drug with selective target and a metal ions, wherein an interaction between the polyphenols, the clinical drug with selective target and the metal ions leading to synergistic effects.
 10. The method of claim 9, wherein the polyphenols is at least one selected from the group comprising tea polyphenols, curcumin, EGCG, theaflavin, apigenin, berberine, quercetin, tannin, catechin, chlorogenic acid, isoflavone, anthocyanidin, cocoa polyphenols, citrin, tetramethylpyrazine, nordihydroguaiaretic acid, flavonoid and resveratrol.
 11. The method of claim 9, wherein the clinical drug with selective target is at least one selected from the group comprising receptor agonists or antagonists, ion channel modulators, membrane ion transporters and mitochondrial functional modulators.
 12. The method of claim 9, wherein the clinical drug with selective target is at least one selected from the group comprising NaF, memantine, metformin, thioridazine, chlorpromazine, tobramycin, rifampin, strepotomycin, isoniazide, verapamil, diltiazem, dithiothretol, dibucaine, digitonin, polymycin B cisplatin, dequalinium, 4-hexylresorcinol, ursodeoxycholic acid, etidronate, glibenclamide and 3,4-diaminopyridine.
 13. The method of claim 9, wherein the metal ions is at least one selected from the group comprising Cu²⁺, Mn²⁺, VO₄ ²⁺, Zn²⁺, Sr²⁺, SeO₃ ⁻², Ag⁺, and RuR.
 14. The method of claim 9, wherein the antimicrobial pathogen is at least one selected from the group comprising Porphyromonas gingivalis, Streptococcus mutans, E. coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphytococcus aureus, MRSA and Mycobacterium tuberculosis etc.
 15. The method of claim 9, wherein the proportion between the concentration of the polyphenols and the clinical drug with selective target is 1:0.1-3. 